2. International Association for Study of Pain
Working together for Pain Relief
"Pain is an unpleasant
sensory and emotional
experience associated
with actual or potential
tissue damage, or
described in terms of
such damage.“
Bonica JJ. The need of a taxonomy. Pain. 1979
4. Descartes Specificity Theory
1649
Large (L) and small (S) fibers are assumed
to
transmit
touch
and
pain
impulses,
respectively,
in
separate, specific, straight-through pathways
to touch and pain centers in the brain (pineal
gland)
5. Goldscheider's summation theory
1894
Convergence of small fibers onto a
dorsal horn cell. The central network
projecting to the central cell.
Touch is assumed to be carried by large
fibers
Livingston proposed model of
reverberatory circuits
Explains pathological chronic pain states
Goldscheider A. Uber den schmerzes in physiologischer and klinicher hinsicht, 1894
6. Sensory interaction theory
by Noordenbos
1959
Multisynaptic afferent system
Large (L) fibers inhibit (−) and small (S) fibers excite (+)
central transmission neurons.
The output projects to spinal cord neurons.
Suggested that the substantia gelatinosa in the dorsal horns
plays a major role in the summation of incoming nerve
impulses
Noordenbos W. Pain. Amsterdam: Elsevier; 1959.
7. Gate Control Theory of Pain
Melzack and Wall
1965
The large (L) and small (S) fibers project to the substantia
gelatinosa (SG) and first central transmission (T) cells.
The central control trigger is represented by a line running
from the large fiber system to central control
mechanisms, which in turn project back to the gate control
system.
The T cells project to the entry cells of the action system.
Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965
9. Conceptual model of the sensory, motivational, and
central control determinants of pain
Melzack R, Casey
KL. Sensory, motivational, and
central control determinants of
pain.
The output of the T (transmission) cells
of the gate control system projects to the
sensory-discriminative system and the
motivational-affective system.
The central control trigger running from
the large fiber system to central control
processes; these, in turn, project back to
the gate control system, and to the
cognitive-evaluative, sensorydiscriminative and motivational-affective
systems.
All three systems interact with one
another, and project to the motor system.
10. Role of Brain in
Pain Generation
Melzack R, Loeser JD. Phantom Body Pain In Paraplegics: Evidence
for a “Central Pattern Generating Mechanism” For Pain. Pain 1978
11. Conclusions from Phantom Limb Observations
•
•
•
•
Brain processes are normally activated and modulated by inputs
from the body but they can act in the absence of any inputs.
The origins of the patterns of experience lie in neural networks
in the brain; stimuli may trigger the patterns but do not produce
them
The body is perceived as a unity and is identified as the „self ‟,
distinct from other people and the surrounding world. This is
produced by central neural processes and cannot derive from
the peripheral nervous system or spinal cord.
The brain processes that underlie the body-self are „built-in‟ by
genetic specification. This built-in substrate is modified by
experience, including social learning and cultural influences
12. NEUROMATRIX THEORY
Melzack R, 1990
Body-self neuromatrix - Network of neurons that consists
of loops between the thalamus and cortex as well as
between the cortex and limbic system
Neurosignature-The repeated cyclical processing and
synthesis of nerve impulses through the neuromatrix imparts
a characteristic pattern
Signature patterns bifurcate
One pattern proceeds to the sentient neural hub –
experience
Second- Proceeds through a action neuromatrix that
activates spinal cord neurons to produce muscle patterns
for complex actions
13. NEUROMATRIX THEORY
Factors that contribute to the
patterns of activity generated by
the body-self neuromatrix.
Neuromatrix comprised of
sensory, affective, and cognitive
neuromodules.
The output patterns from the
neuromatrix produce the
multiple dimensions of pain
experience, as well as concurrent
Melzack R. Phantom limbs and the homeostatic and behavioral
concept of neuromatrix.
responses.
Trend Neurosci 1990,
14. Action-Neuromatrix
Action matrix activates appropriate action
patterns for experience.
Cyclical processing and synthesis produces
activation of several possible patterns
Some of them are eliminated until one particular
pattern emerges as the most appropriate for the
circumstances at the moment
Permits a smooth, continuous stream of action
patterns.
15. From the neuromatrix to the pain matrix
Main components of Pain
Matrix
• Primary and secondary
somatosensory cortex
• Insular Cortex
• Anterior cingulate Cortex
• Prefrontal cortices
• Thalamus (Th)
Apkarian AV et al. Human brain mechanisms of pain perception and
regulation in health and disease. Eur J Pain. 2005
16. Applications of Neuromatrix theory
Phantom Limb Pain
De-afferentation absence of modulating
inputs from the limbs in the or body
Active body-neuromatrix,, produces a
neurosignature
pattern
highfrequency, bursting pattern is transduced in
the sentient neural hub into a hot or burning
quality.
17. Applications of Neuromatrix theory
Low back Ache
Perpetual stresses and strains on the
vertebral
column
release
of
Inflammation and pain Mediators cortisol and norepinephrine activate a
neuromatrix program generates the
neurosignature for pain
18. Applications of Neuromatrix theory
Fibromyalgia
Body-self neuromatrix's response
to stressful events fails to turn
off when the stressor diminishes
neuromatrix maintains a
continuous state of alertness to
threat Readiness for action
22. Nociceptors
Subdivision Aδ nociceptors
Type I (HTM: high-threshold
mechanical nociceptors)
Respond to mechanical and
chemical stimuli, high heat thresholds
(>50 C).
Type II Aδ nociceptors
Lower heat threshold, very high
mechanical threshold
23. Nociceptors
Unmyelinated C fibers
Heterogeneous, Polymodal
More responsive to chemical stimuli
Peptidergic” C nociceptors
-releases the neuropeptides, substance
P, and calcitonin-gene related peptide
(CGRP)
TrkA neurotrophin receptor that responds
to nerve growth factor (NGF).
Nonpeptidergic C nociceptors
express c-Ret neurotrophin receptor
Targetted
by
glial-derived
neurotrophic factor (GDNF), neurturin and
artemin
24. Activation of the Nociceptors
Heat
• Heat- Threshold ∼ 430
•
- Capsaicin receptor, TRPV1
• Cold- Threshold of ∼25 C
•
- TRPM8
• Voltage-gated sodium channels and
potassium channels fine tune thresholds
• Receptors may be gated
25. Activation of the Nociceptors
Mechanical Stimuli
• TRP Channels- TRPA1, TRPV2 and
TRPV4
• KCNK Channels
26. Activation of the Nociceptors
Chemical
Exogenous
irritantspollutants, chemicals
TRP channels
environmental
• TRPA1 responds to compounds that are structurally
diverse substances
• Anesthetics(isoflurane), chemotherapeutic
agents(cyclophosphomide)- excplains pain and
neuroinflammation
• Channel gating -allyl isothiocyanate (from wasabi) or
allicin (from garlic) activate TRPA1 by covalently
modifying cysteine residues within the channel
27. • Endogenous Stimulants
• Endogenous irritants (produced in response to tissue
damage or physiological stress, oxidative stress)
• Activated Nociceptors
• Non-neural Cells - Infiltrate into the Injured Area
• Mast Cells, Basophils, Platelets, Macrophages, Neutrophils, Endothelial
Cells, Keratinocytes, and Fibroblasts)
• Inflammatory soup
• Neurotransmitters- Glutamate
• Peptides- SubstanceP, CGRP, bradykinin)
• Eicosinoids and related lipids
(prostaglandins, thromboxanes, leukotrien
es, endocannabinoids)
• Neurotrophins (NGF), cytokines, and
chemokines,
• Extracellular proteases and protons.
Nociceptors- G protein-coupled receptors (GPCR), TRP channels, acid-sensitive ion
channels (ASIC), two-pore potassium channels (K2P), and receptor tyrosine kinases(RTK)
28. Reducing Inflammatory Pain
Inhibiting the synthesis or
accumulation of components of
the inflammatory soup
Block the actions of inflammatory
agents at the nociceptor Basis
of new therapeutic strategies for
treating inflammatory pain
29. Nociceptors
Unique Property-Bidirectional Signalling
Peripheral terminal releases a variety of
molecules that influence the local tissue
environment
Peripheral release of the neuropeptides, CGRP
and substance P Induces vasodilation and
extravasation of plasma proteins Neurogenic
inflammation
Implication-Therapeutics directed at both
terminals can be developed to influence the
transmission of pain messages
30. Mechanisms of Peripheral Sensitization
Enhance excitability of the nociceptor and amplify
the neurogenic inflammatory response.
Nerve growth factor (NGF)
Retrogradely transported to the nucleus of the nociceptor
•
NGF-TrkA interaction activates downstream signaling
pathways
•
Promotes increased expression of pronociceptive proteins(substance
P, TRPV1, and the Nav1.8 )
Cytokines- Interleukin-1β (IL-1β) and IL-6, and TNF-α
•
Potentiation of the inflammatory response and increased
production
of
proalgesic
agents
(such
as
prostaglandins, NGF, bradykinin, and extracellular protons)
31. Interfering with neurotrophin or cytokine
signaling - Major strategy for controlling
inflammatory disease or resulting pain
F.F. Hefti et al. Novel class of pain drugs based
on antagonism of NGF. Trends Pharmacol. Sci. (2006)
F. Atzeni et al. Autoimmunity and anti-TNFalpha agents. Ann. N Y Acad. Sci. (2005)
32. Mechanisms of Peripheral Sensitization
• TRPV1 modulation
•
•
Relevant to tissue injury-evoked pain
hypersensitivity
Inflammation Pain(sunburn, infection, rheumatoid or
osteoarthritis, and inflammatory bowel disease)
Genetic or pharmacological blockade of
TRPA1 reduces inflammatory pain
33. Conducting the Pain Signal
Voltage-Gated Sodium Channels
• TTX-sensitive channels: Nav1.1, 1.6, and
1.7
•
Nav1.7 Altered activity leads human pain
disorders- erythromelalgia and paroxysmal
extreme pain disorder
• TTX-resistant channels: Nav1.8 and 1.9.
•
Nav1.8 sodium channel is highly expressed by
most C nociceptors
KCNQ potassium channels
34. Applications of Voltage-gated channels
Targets of local anesthetic drugs-Potential for the
development of subtype-specific analgesics.
Nav1.7 - Target for treating inflammatory pain syndromes
Nav1.7 inhibitors should reduce pain without altering other
essential physiological processes
Nav1.8 (or TRPM8) antagonists -Treat cold allodynia
(extreme hypersensitivity to cold-adverse side effect of
platinum-based chemotherapeutics (oxaliplatin)
Treatment of neuropathic pain by Antidepressant serotonin
and norepinephrine reuptake inhibitors result from their
ability to block voltage gated sodium channels
Increasing K+ channel activity for the treatment of persistent
pain
35. Voltage-Gated Calcium Channels
• N-, P/Q-, and T-type calcium channels
•
•
•
P/Q-type channels are expressed at synaptic
terminals in laminae II–IV of the dorsal horn
Mutations in these channels have been linked to
familial hemiplegic migraine
N- and T-type calcium channels are upregulated
under pathophysiological states (diabetic
neuropathy or after other forms of nerve injury)
36. Voltage-Gated Calcium Channels
• Ca channels composed of α1 pore
forming subunits and the modulatory
subunits α2δ, α2β, α2γ.
•
•
α2δ subunit regulates current density and kinetics
of activation and inactivation.
α2δ subunit of C nociceptors - upregulated after
nerve injury and plays a key role in injury-evoked
hypersensitivity and allodynia
Target of the gabapentinoid class of
anticonvulsants used to treat neuropathic pain
37. Alterations in the properties of peripheral nerves
•
•
Inflammation-associated changes in the chemical
environment of the nerve fiber Peripheral
sensitization
Damage to nerve fibers (Injury or diseases
(diabetes, arthritis, or tumor growth) Increased
spontaneous firing/ Alterations in their
conduction or neurotransmitter properties
Persistent pain
Application- Topical and even systemic local anesthetics for
the treatment of different neuropathic pain conditions
38. Organization of Projection of Afferent Pain Fibres
into the Dorsal Horn of Spinal Cord
Injury Induced
persistent Pain
Referred Pain
39. Central sensitization
Process through which a state of hyperexcitability is
established in the central nervous system, leading to
enhanced processing of nociceptive (pain) messages
Mechanisms
• Glutamatergic neurotransmission/NMDA receptormediated hypersensitivity
• Loss of tonic inhibitory controls (disinhibition)
• Glial-neuronal interactions
42. Transmission and Control of Pain Messages
Selectivity present
mu opioid receptor (MOR) expressed in the
peptidergic nociceptors
delta opioid receptor (DOR) is expressed in
nonpeptidergic nociceptors
MOR-selective agonists block heat pain
DOR- selective agonists block mechanical
pain
43. Opioid receptors
Belong to the family of transmembrane G-protein coupled
receptors (GPCR)
Expressed by central and peripheral neurons, by
neuroendocrine (pituitary, adrenals), immune, and
ectodermal cells
International Union of Pharmacology (IUPHAR) Receptor
Classification
MOP (mu),
KOP (kappa)
DOP (delta)
NOP (nociceptin orphanin FQ peptide receptor)
44. Structures/molecules involved in peripheral opioid-mediated analgesia.
Melanie Busch-Dienstfertig , Christoph Stein Opioid receptors and opioid peptide-producing
leukocytes in inflammatory pain – Basic and therapeutic aspects Brain, Behavior, and Immunity 2010
45. New Areas of Research
Development of opioid drugs unable to pass
the blood–brain barrier
Inhibition of inflammation by peripherally
acting opioid drugs
Selective targeting of opioid peptideproducing cells to sites of injury
Augmentation of opioid peptide
synthesis by gene transfer
46. Pain and Neuroplasticity
•
•
•
•
•
Plasticity- Neuronal and synaptic functions are
capable of being molded or shaped so that they
influence subsequent perceptual experiences
Plasticity related to pain - Persistent functional
changes, or „somatic memories‟ produced in the
nervous system by injuries or other pathological
events.
A labeled line system might not accommodate
such plasticity
Alterations in such mechanisms underlie
maladaptive changes that produce chronic pain
Essential to understanding chronic pain
syndromes
47. Gene-based approaches in pain research
JennyMolet, MichelPohl.
Gene-based approaches in
pain research and exploration of new
therapeutic targets and strategies. European
Journal of Pharmacology (2013)
48. Psychological generation in pain
Pain and Psychopathology
Neurophysiological mechanisms that involve an
interplay between peripheral and central neural
activity
• Pain in „nonanatomical‟ distribution
• Spread of pain to non-injured territory
• Pain out of proportion to the degree of
injury
• Pain in the absence of injury
• Mirror Image Pain
49. Pain and Stress
Pain „stress‟ Reinstate homeostasis
Release
of
CytokinesGammainterferon, interleukins 1 and 6, tumor
necrosis factor
Locus coeruleus/norepinephrine system
activated –Sympathetic system activated.
Hypothalamic–pituitary–adrenal (HPA) system
activated - release of cortisol
Sensitivity to pain traumatization (SPT) vulnerability factor for chronic postsurgical
50. Application of Pain Physiology
Intense noxious stimulation produces a
sensitization of CNS neurons
• Reduction in acute pain intensity translates
into reduced pain and pain disability
• Development of longer term neuropathic
pain also can be prevented by reducing the
potential for central sensitization at the time
of injury
• Target treatments not only at the site of
peripheral tissue damage but also at the site
of central changes
53. A TRIBUTE TO RONALD MELZACK
A KING OF UNDERSTANDING PAIN
“The future is research on how the brain creates our world: the world we see, hear, touch and feel.
Pain is the doorway into that.”
Editor's Notes
We all know that pain has many valuable functions. It often signals injury or disease and generates a wide range of behaviors to end it and to treat its causes. Chest pain, for example, may be a symptom of heart disease, and may compel us to seek a physician's help. Memories of past pain and suffering also serve as signals for us to avoid potentially dangerous situations. Yet another beneficial effect of pain, notably after serious injury or disease, is to make us rest, thereby promoting the body's healing processes. All of these actions induced by pain—to escape, avoid, or rest—have obvious value for survival.Despite these beneficial aspects of pain, there are negative features that challenge our understanding of the puzzle of pain. What is the benefit of chronic phantom limb pain to an amputee whose stump has healed completely? The pain, not the physical impairment, prevents them from leading a normal life. Likewise, most backaches, headaches, muscle pains, nerve pains, pelvic pains, and facial pains serve no discernible purpose, are resistant to treatment, and are a catastrophe for the people who are afflicted.Pain may be the warning signal that saves the lives of some people, but it destroys the lives of countless others. Chronic pains, clearly, are not a warning to prevent physical injury or disease. They are the disease—the result of neural mechanisms gone awry.1–3 In this section, we review past and current theories of pain,
We all know that pain has many valuable functions. It often signals injury or disease and generates a wide range of behaviors to end it and to treat its causes. Chest pain, for example, may be a symptom of heart disease, and may compel us to seek a physician's help. Memories of past pain and suffering also serve as signals for us to avoid potentially dangerous situations. Yet another beneficial effect of pain, notably after serious injury or disease, is to make us rest, thereby promoting the body's healing processes. All of these actions induced by pain—to escape, avoid, or rest—have obvious value for survival.Pain may be the warning signal that saves the lives of some people, but it destroys the lives of countless others. What is the benefit of chronic phantom limb pain, Likewise, most backaches, headaches, muscle pains, nerve pains, pelvic pains, and facial pains serve no discernible purpose, are resistant to treatment, and are a catastrophe for the people who are afflicted. The pain, not the physical impairment, prevents them from leading a normal life. Despite these beneficial aspects of pain, there are negative features that challenge our understanding of the puzzle of pain. Understanding the pain pathways and signal transmission may help us solve this. The definition of pain
The theory of pain we inherited in the 20th century was proposed by Descartes three centuries earlier. Descartes’ proposition that pain derives from nociceptive projections onto the pinealgland, as a specific, direct-line sensory projection system. ’’(Descartes1649) The impact of Descartes' specificity theory was enormous. It influenced experiments on the anatomy and physiology of pain up to the first half of the 20th century. Descartes' specificity theory, then, determined the ‘facts’ as they were known up to the middle of the 20th century, and even determined therapy. This rigid anatomy of pain in the 1950s led to attempts to treat severe chronic pain by a variety of neurosurgical lesions. Specificity theory proposed that injury activates specific pain receptors and fibers which, in turn, project pain impulses through a spinal pain pathway to a pain center in the brain. The psychological experience of pain, therefore, was virtually equated with peripheral injury. In the 1950s, there was no room for psychological contributions to pain, such as attention, past experience, anxiety, depression, and the meaning of the situation. Instead, pain experience was held to be proportional to peripheral injury or pathology. Patients who suffered back pain without presenting signs of organic disease were often labeled as psychologically disturbed and sent to psychiatrists. The concept was simple and often failed to help patients who suffered severe chronic pain. To thoughtful clinical observers,5,6 specificity theory was clearly wrong. There were several attempts to find a new theory.
Goldscheider7 proposed that central summation in the dorsal horns is one of the critical determinants of pain. Livingston5 postulated a reverberatory circuit in the dorsal horns to explain summation, referred pain and pain that persisted long after healing was completed..
Noordenbos8 proposed that large-diameter fibers inhibited small-diameter fibers, and he even suggested that the substantiagelatinosa in the dorsal horns plays a major role in the summation of incoming nerve impulses and other dynamic processes described by Livingston.5 However, in none of these theories was there an explicit role for the brain other than as a passive receiver of messages. Nevertheless, the successive theoretical concepts moved the field in the right direction: into the spinal cord and away from the periphery as the exclusive answer to pain. At least the field of pain was making its way up toward the brain
Theories of pain, like all scientific theories, evolve as result of the accumulation of new facts as well as leaps of the imagination.In 1965, Melzack and Wall11 proposed the gate control theory of pain. The final model, depicted in Figure 1(d), is the first theory of pain to incorporate the central control processes of the brain.The gate control theory of pain11 proposed that the transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a gating mechanism in the spinal dorsal horn. This gating mechanism is influenced by the relative amount of activity in large- and small-diameter fibers, so that large fibers tend to inhibit transmission (close the gate) while small-fibers tend to facilitate transmission (open the gate). In addition, the spinal gating mechanism is influenced by nerve impulses that descend from the brain. When the output of the spinal T cells exceeds a critical level, it activates the Action System—those neural areas that underlie the complex, sequential patterns of behavior and experience characteristic of pain.The theory's emphasis on the modulation of inputs in the spinal dorsal horns and the dynamic role of the brain in pain processes had a clinical as well as a scientific impact. Psychological factors, which were previously dismissed as ‘reactions to pain’, were now seen to be an integral part of pain processing and new avenues for pain control by psychological therapies were opened. Similarly, cutting nerves and pathways were gradually replaced by a host of methods to modulate the input. Physical therapists and other health-care professionals were brought into the picture, and transcutaneous electrical nerve stimulation became an important modality for the treatment of chronic and acute pain. The current status of pain research and therapy indicates that, despite the addition of a massive amount of detail, the conceptual components of the theory have stood the test of time.12
It is evident that the gate control theory has taken us a long way. Yet, as historians of science have pointed out, good theories are instrumental in producing facts that eventually require a new theory to incorporate them. And this is what has happened. It is possible to make adjustments to the gate theory so that, for example, it includes long-lasting activity of the sort Wall has described
We believe the great challenge ahead of us is to understand brain function. Melzack and Casey13 made a start by proposing that specialized systems in the brain are involved in the sensory-discriminative, motivational-affective and cognitive-evaluative dimensions of subjective pain experience (Figure 2). These names for the dimensions of subjective experience seemed strange when they were coined, but they are now used so frequently and seem so ‘logical’ that they have become part of our language. So too, the McGill Pain Questionnaire, which taps into subjective experience—one of the functions of the brain—is the most widely used to instrument to measure pain.14–16 The newest version, the Short-Form McGill Pain Questionnaire-2,16 was designed to measure the qualities of both neuropathic and non-neuropathic pain in research and clinical settings.
(see Ref 4). But there is a set of observations on pain in paraplegic patients that just does not fit the theory. This does not negate the gate theory, of course. Peripheral and spinal processes are obviously an important part of pain and we need to know more about the mechanisms of peripheral inflammation, spinal modulation, midbrain descending control, and so forth. But the data on painful phantoms below the level of total spinal cord section18,19 indicate that we need to go above the spinal cord and into the brain.n 1978, Melzack and Loeser17 described severe pains in the phantom body of paraplegic patients with verified total sections of the spinal cord, and proposed a central ‘pattern generating mechanism’ above the level of the section. This concept represented a revolutionary advance: it did not merely extend the gate; it said that pain could be generated by brain mechanisms in paraplegic patients in the absence of a spinal gate because the brain is completely disconnected from the cord. Psychophysical specificity, in such a concept, makes no sense; instead we must explore how patterns of nerve impulses generated in the brain can give rise to somesthetic experience.spinal projection areas in the thalamus and cortex. These areas are important, of course, but they are only part of the neural processes that underlie perception. The cortex, Gybels and Tasker made amply clear, is not the pain center and neither is the thalamus.20 The areas of the brain involved in pain experience and behavior must include somatosensory projections as well as the limbic system. Furthermore, cognitive processes are known to involve widespread areas of the brain. Despite this increased knowledge, we do not have yet an adequate theory of how the brain works.
Melzack's19 analysis of phantom limb phenomena, particularly the astonishing reports of a phantom body and severe phantom limb pain in people with a total thoracic spinal cord section,17 led to four conclusions which pointed to a new conceptual model of the nervous system. First, because the phantom limb feels so real, it is reasonable to conclude that the body we normally feel is subserved by the same neural processes in the brain as the phantom; these brain processes are normally activated and modulated by inputs from the body but they can act in the absence of any inputs. Second, all the qualities of experience we normally feel from the body, including pain, are also felt in the absence of inputs from the body; from this we may conclude that the origins of the patterns of experience lie in neural networks in the brain; stimuli may trigger the patterns but do not produce them. Third, the body is perceived as a unity and is identified as the ‘self’, distinct from other people and the surrounding world. The experience of a unity of such diverse feelings, including the self as the point of orientation in the surrounding environment, is produced by central neural processes and cannot derive from the peripheral nervous system or spinal cord. Fourth, the brain processes that underlie the body-self are ‘built-in’ by genetic specification, although this built-in substrate must, of course, be modified by experience, including social learning and cultural influences. These conclusions provide the basis of the conceptual model18,19,21 depicted in Figure 3.
The anatomical substrate of the body-self is a large, widespread network of neurons that consists of loops between the thalamus and cortex as well as between the cortex and limbic system.18,19,21 The entire network, whose spatial distribution and synaptic links are initially determined genetically and are later sculpted by sensory inputs, is a neuromatrix. The loops diverge to permit parallel processing in different components of the neuromatrix and converge repeatedly to permit interactions between the output products of processing. The experience of the body-self involves multiple dimensions—sensory, affective, evaluative, postural and many others. The sensory dimensions are subserved, in part at least, by portions of the neuromatrix that lie in the sensory projection areas of the brain; the affective dimensions are subserved by areas in the brainstem and limbic system. Each major psychological dimension (or quality) of experience is subserved by a particular portion of the neuromatrix which contributes a distinct portion of the total neurosignatureThe repeated cyclical processing and synthesis of nerve impulses through the neuromatrix imparts a characteristic pattern: the neurosignature. The neurosignature of the neuromatrix is imparted on all nerve impulse patterns that flow through it; the neurosignature is produced by the patterns of synaptic connections in the entire neuromatrix. All inputs from the body undergo cyclical processing and synthesis so that characteristic patterns are impressed on them in the neuromatrix. Portions of the neuromatrix are specialized to process information related to major sensory events (such as injury, temperature change and stimulation of erogenous tissue) and may be labeled as neuromodules which impress sub signatures on the larger neurosignature.We do not learn to feel qualities of experience: our brains are built to produce them. The inadequacy of the traditional peripheralist view becomes especially evident when we consider paraplegic patients with high-level complete spinal cord transections. In spite of the absence of inputs from the body, virtually every quality of sensation and affect is experienced. It is known that the absence of input produces hyperactivity and abnormal firing patterns in spinal cells above the level of the break.17 But how, from this jumble of activity, do we get the meaningful experience of movement, the coordination of limbs with other limbs, cramping pain in specific muscle groups, and so on? This must occur in the brain, in which neurosignatures are produced by neuromatrixes that are triggered by the output of hyperactive cellsWhen all sensory systems are intact, inputs modulate the continuous neuromatrix output to produce the wide variety of experiences we feel. We may feel position, warmth, and several kinds of pain and pressure all at once. It is a single unitary feeling just as an orchestra produces a single unitary sound at any moment even though the sound comprises violins, cellos, horns, and so forth. Similarly, at a particular moment in time we feel complex qualities from all of the body. In addition, our experience of the body includes visual images, affect, ‘knowledge’ of the self (versus not-self) as well as the meaning of body parts in terms of social norms and values. It is hard to imagine of all of these bits and pieces coming together to produce a unitary body-self, but we can conceive of a neuromatrix which impresses a characteristic signature on all the inputs that converge on it and thereby produces the never-ending stream of feeling from the body.The neurosignature, which is a continuous output from the body-self neuromatrix, is projected to areas in the brain—the sentient neural hub—in which the stream of nerve impulses (the neurosignature modulated by ongoing inputs) is converted into a continually changing stream of awareness. Furthermore, the neurosignature patterns may also activate a second neuromatrix to produce movement, the action-neuromatrix . That is, the signature patterns bifurcate so that a pattern proceeds to the sentient neural hub (where the pattern is transformed into the experience of movement) and a similar pattern proceeds through a neuromatrix that eventually activates spinal cord neurons to produce muscle patterns for complex actionsThe body is felt as a unity, with different qualities at different times. The brain mechanism that underlies the experience also comprises a unified system that acts as a whole and produces a neurosignature pattern of a whole body.18,19,21 The conceptualization of this unified brain mechanism lies at the heart of the theory, and the word ‘neuromatrix’ best characterizes it. The neuromatrix (not the stimulus, peripheral nerves or ‘brain center’) is the origin of the neurosignature; the neurosignature originates and takes form in the neuromatrix. Though the neurosignature may be activated or modulated by input, the input is only a ‘trigger’ and does not produce the neurosignature itself. The neuromatrix ‘casts’ its distinctive signature on all inputs (nerve impulse patterns) which flow through it. Finally, the array of neurons in a neuromatrix is genetically programmed to perform the specific function of producing the signature pattern. The final, integrated neurosignature pattern for the body-self ultimately produces awareness and action.The neuromatrix, distributed throughout many areas of the brain, comprises a widespread network of neurons which generates patterns, processes information that flows through it, and ultimately produces the pattern that is felt as a whole body. The stream of neurosignature output with constantly varying patterns riding on the main signature pattern produces the feelings of the whole body with constantly changing qualities the neural networks proposed by Hebb22 and Bindra23 developed by gradual sensory learning, whereas Melzack, instead, conceived the structure of the neuromatrix to be predominantly determined by genetic factors, although its eventual synaptic architecture is influenced by sensory inputs. This emphasis on the genetic contribution to the brain does not diminish the importance of sensory inputs. The neuromatrix is a psychologically meaningful unit, developed by both heredity and learning, that represents an entire unified entity.
t is difficult to comprehend how individual bits of information from skin, joints, or muscles can all come together to produce the experience of a coherent, articulated body. At any instant in time, millions of nerve impulses arrive at the brain from all the body's sensory systems, including the proprioceptive and vestibular systems. How can all this be integrated in a constantly changing unity of experience? Where does it all come together?Melzack18,19,21 conceptualized a genetically built-in neuromatrix for the whole body, producing a characteristic neurosignature for the body which carries with it patterns for the myriad qualities we feel. The neuromatrix produces a continuous message that represents the whole body in which details are differentiated within the whole as inputs come into it. We start from the top, with the experience of a unity of the body, and look for differentiation of detail within the whole. The neuromatrix, then, is a template of the whole, which provides the characteristic neural pattern for the whole body (the body's neurosignature) as well as subsets of signature patterns (from neuromodules) that relate to events at (or in) different parts of the body.The command, which originates in the brain, to perform an action such as running activates the neuromodule which then produces firing in sequences of neurons that send precise messages through ventral horn neuron pools to appropriate sets of muscles. At the same time, the output patterns from the body-neuromatrix that engage the neuromodules for particular actions are also projected to the sentient neural hub and produce experience. In this way, the brain commands may produce the experience of movement of phantom limbs even though there are no limbs to move and no proprioceptive feedbackThe phenomenon of phantom limbs has allowed us to examine some fundamental assumptions in psychology. One assumption is that sensations are produced only by stimuli and that perceptions in the absence of stimuli are psychologically abnormal. Yet phantom limbs, as well as phantom seeing,26 indicate this notion is wrong. The brain does more than detect and analyze inputs; it generates perceptual experience even when no external inputs occur.Another entrenched assumption is that perception of one's body results from sensory inputs that leave a memory in the brain; the total of these signals becomes the body image. But the existence of phantoms in people born without a limb or who have lost a limb at an early age suggests that the neural networks for perceiving the body and its parts are built into the brain.18,19,27,28 The absence of inputs does not stop the networks from generating messages about missing body parts; they continue to produce such messages throughout life. In short, phantom limbs are a mystery only if we assume the body sends sensory messages to a passively receiving brain. Phantoms become comprehensible once we recognize that the brain generates the experience of the body. Sensory inputs merely modulate that experience; they do not directly cause it.
The output of the body neuromatrix is directed at two systems: (1) the neuromatrix that produces awareness of the output, and (2) a neuromatrix involved in overt action patterns. Just as there is a steady stream of awareness, there is also a steady output of behavior (including movements during sleep). It is important to recognize that behavior occurs only after the input has been at least partially synthesized and recognized. For example, when we respond to the experience of pain or itch, it is evident that the experience has been synthesized by the body-self neuromatrix (or relevant neuromodules) sufficiently for the neuromatrix to have imparted the neurosignature patterns that underlie the quality of experience, affect and meaning. Most behavior occurs only after inputs have been analyzed and synthesized sufficiently to produce meaningful experience. When we reach for an apple, the visual input has clearly been synthesized by a neuromatrix so that it has 3-dimensional shape, color and meaning as an edible, desirable object, all of which are produced by the brain and are not in the object ‘out there’. When we respond to pain (by withdrawal or even by telephoning for an ambulance), we respond to an experience that has sensory qualities, affect and meaning as a dangerous (or potentially dangerous) event to the body.After inputs from the body undergo transformation in the body-neuromatrix, the appropriate action patterns are activated concurrently (or nearly so) with the neuromatrix for experience. Thus, in the action-neuromatrix, cyclical processing and synthesis produces activation of several possible patterns, and their successive elimination, until one particular pattern emerges as the most appropriate for the circumstances at the moment. In this way, input and output are synthesized simultaneously, in parallel, not in series. This permits a smooth, continuous stream of action patterns.
The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions it is the pattern of activation in the different structures of the Pain Matrix thatconstitutes, as an ensemble, the neural substrate for painperception. In this view, the emergence of pain would notresult from the activation of one or more specific brainareas but would emerge ‘‘from the flow and integration of information’’ among these areas (Tracey2005). Therefore,this view is different from the original Neuromatrix con-cept only in the sense that the experience of pain is con-sidered as the only possible output of the network. Othershave deviated further from the original concept, by con-sidering the Pain Matrix as an enumeration of differentpain-specific structures of the brain concept of pain specificity, we show that the fraction of the neuronal activity measured using currently availablemacroscopic functional neuroimaging techniques (e.g.,EEG, MEG, fMRI, PET) in response to transient
ow back pain is one of the most common types of pain, yet it is poorly understood. It illustrates the complexity of interactions among different contributing factors and the need for multiple approaches to treat it.76 Protruding discs, arthritis of vertebral joints, tumors, and fractures are known to cause low back pain. However, about 60–70% of patients who suffer severe low back pain show no evidence of disc disease, arthritis, or any other symptoms that can be considered the cause of the pain. Even when there are clear-cut physical and neurological signs of disc herniation (in which the disc pushes out of its space and presses against nerve roots), surgery produces complete relief of back pain and related sciatic pain in only about 60% of cases. The rate of success in different reports ranges from 50 to 95%, depending in part on the spatial distribution of the pain. Furthermore, patients with physical signs such as disc herniation in the lower spine are rarely helped by surgical procedures such as fusion of several vertebrae to provide structural support to the back.76 A variety of forms of physical therapy are more likely to help low back pain. The most effective is a regimen of exercises that develops the back muscles. Transcutaneous electrical nerve stimulation, ice massage, and acupuncture may also help some patients. Injections of anesthetics into trigger points may be effective as well. Still, despite all of these therapies, many patients continue to suffer severe, unrelenting pain.77A high proportion of cases of chronic back pain may be due to more subtle causes. The perpetual stresses and strains on the vertebral column (at discs and adjacent structures called facet joints) produce an increase in small blood vessels and fibrous tissue in the area.78 As a result, there is a release of substances that are known to produce inflammation and pain into local tissues and the blood stream; this whole stress cascade may be triggered repeatedly. The effect of stress-produced substances—such as cortisol and norepinephrine—at sites of minor lesions and inflammation could, if it occurs often and is prolonged, activate a neuromatrix program that anticipates increasingly severe damage and attempts to counteract it. The program to reduce strain and inflammation could include generating the neurosignature for pain—part of a neural program which presumably evolved to induce rest, the repair of injured tissues, and the restoration of homeostasis.As a result of the persistence of low back pain despite all the available therapies, it is not surprising that psychological interventions, such as relaxation therapy, Cognitive-Behavior Therapy, and Acceptance and Commitment Therapy have become an important approach to the problem. But no one therapy is more effective than the others. In fact, clinics often employ several procedures at the same time to get the best results.7
Tissue destruction, abnormal immune reactivity, and/or nerve injury are frequently associated with an inflammatory response.
The primary afferent nerve fiber detects environmental stimuli (of a thermal, mechanical, or chemical nature) and transduces this information into the language of the nervous system, namely electrical current. Nociception is the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the body and the trigeminal ganglion for the face, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess biophysical and molecular properties that enable them to detect selectively and respond to potentially injurious stimuli. There are two major classes of nociceptors (Meyer et al., 2008). The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e., light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain.After synaptic transmission and modulation within the primary sensory neuron and spinal cord, nociceptive signals reach the brain, where they are finally perceived as “pain“ within the context of cognitive and environmental factors
Electrophysiological studies have further subdivided Aδnociceptors into two main classes. Type I (HTM: high-threshold mechanical nociceptors) respond to both mechanical and chemical stimuli but have relatively high heat thresholds (>50°C). If, however, the heat stimulus is maintained, these afferents will respond at lower temperatures. And most importantly, they will sensitize (i.e., the heat or mechanical threshold will drop) in the setting of tissue injury. Type II Aδnociceptors have a much lower heat threshold, but a very high mechanical threshold. Activity of this afferent almost certainly mediates the “first” acute pain response to noxious heat. Indeed, compression block of myelinated peripheral nerve fibers eliminates first, but not second, pain. By contrast, the type I fiber likely mediates the first pain provoked by pinprick and other intense mechanical stimuli.
unmyelinated C fibers are also heterogeneous. Like the myelinated afferents, most C fibers are polymodal, that is, they include a population that is both heat and mechanically sensitive (CMHs) (Perl, 2007). These afferents are more responsive to chemical stimuli (capsaicin or histamine)Neuroanatomical and molecular characterization of nociceptors has further demonstrated their heterogeneity, particularly for the C fibers (Snider and McMahon, 1998). For example, the so-called “peptidergic” population of C nociceptors releases the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP); they also express the TrkAneurotrophin receptor, which responds to nerve growth factor (NGF). The nonpeptidergic population of C nociceptors expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor (GDNF), as well as neurturin and artemin). As noted below, these functionally and molecularly heterogeneous classes of nociceptors associate with specific function in the detection of distinct pain modalities.
Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (TRPV1), cold (TRPM8), acidic milieu (ASICs), and a host of chemical irritants (TRPA1) (Julius and Basbaum, 2001
. Polymodalnociceptors also express chemoreceptors (e.g. TRPA1) and one or more as yet unidentified mechanotransduction channels. These fibers also express a host of sodium channels (such as NaV 1.8 and 1.9) and potassium channels (such as TRAAK and TREK-1) that modulate nociceptor excitability and/or contribute to action potential propagation.the molecular basis of mammalian mechanotransduction is far from clarified. Mechanical hypersensitivity in response to tissue or nerve injury represents a major clinical problem, and thus elucidating the biological basis of touch under normal and pathophysiological conditions remains one of the main challenges in somatosensory and pain research.
Chemo-nociception is the process by which primary afferent neurons detect environmental irritants and endogenous factors produced by physiological stress. In the context of acute pain, chemo-nociceptive mechanisms trigger aversive responses to a variety of environmental irritants.Such factors can act alone, or in combination, to sensitize nociceptors to thermal and/or mechanical stimuli, thereby lowering pain thresholds. The result of this action is to enhance guarding and protective reflexes in the aftermath of injury. Thus, chemo-nociception represents an important interface between acute and persistent pain, especially in the context of peripheral tissue injury and inflammation, as discussed in greater detail below.
Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or nonneural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively, these factors, referred to as the “inflammatory soup,” represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell-surface receptors capable of recognizing and responding to each of these proinflammatory or proalgesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.
approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization or that form the basis of new therapeutic strategies for treating inflammatory pain
One generally thinks of the nociceptor as carrying information in one direction, transmitting noxious stimuli from the periphery to the spinal cord. However, primary afferent fibers have a unique morphology, called pseudo-unipolar, wherein both central and peripheral terminals emanate from a common axonal stalk. The majority of proteins synthesized by the DRG or trigeminal ganglion cell are distributed to both central and peripheral terminals. This distinguishes the primary afferent neuron from the prototypical neuron, where the recipient branch of the neuron (the dendrite) is biochemically distinct from the transmission branch (the axon). The biochemical equivalency of central and peripheral terminals means that the nociceptor can send and receive messages from either end. For example, just as the central terminal is the locus of Ca2+-dependent neurotransmitter release, so the peripheral terminal releases a variety of molecules that influence the local tissue environment. Neurogenic inflammation, in fact, refers to the process whereby peripheral release of the neuropeptides, CGRP and substance P, induces vasodilation and extravasation of plasma proteins, respectively (Basbaum and Jessell, 2000). Furthermore, whereas only the peripheral terminal of the nociceptor will respond to environmental stimuli (painful heat, cold, and mechanical stimulation), both the peripheral and central terminals can be targeted by a host of endogenous molecules (such as pH, lipids, and neurotransmitters) that regulate its sensitivity. It follows that therapeutics directed at both terminals can be developed to influence the transmission of pain messages. For example, spinal (intrathecal) delivery of morphine targets opioid receptors expressed by the central terminal of nociceptors, whereas topically applied drugs (such as local anesthetics or capsaicin) regulate pain via an action at the peripheral terminal.
addition to neurotrophins, injury promotes the release of numerous cytokines, chief among them interleukin-1β (IL-1β) and IL-6, and tumor necrosis factor α (TNF-α) (Ritner et al., 2009). Although there is evidence to support a direct action of these cytokines on nociceptors, their primary contribution to pain hypersensitivity results from potentiation of the inflammatory response and increased production of proalgesic agents (such as prostaglandins, NGF, bradykinin, and extracellular protons).Irrespective of their pronociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-α action with a neutralizing antibody. In the case of TNF-α, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).).
Once thermal and mechanical signals are transduced by the primary afferent terminal, the receptor potential activates a variety of voltage-gated ion channels. Voltage-gated sodium and potassium channels are critical to the generation of action potentials that convey nociceptor signals to synapses in the dorsal horn.. We restrict our discussion to members of the sodium and calcium channel families that serve as targets of currently used analgesic drugs, or for which human genetics support a role in pain transmission. A recent review has discussed the important contribution of KCNQ potassium channels, including the therapeutic benefit of increasing K+ channel activity for the treatment of persistent pain Nav1.7 has received much attention, as altered activity of this channel leads to a variety of human pain disorders
Voltage-gated calcium channels play a key role in neurotransmitter release from central or peripheral nociceptor terminals to generate pain or neurogenic inflammation, respectively
Persistent pain associated with injury or diseases (such as diabetes, arthritis, or tumor growth) can result from alterations in the properties of peripheral nerves. This can occur as a consequence of damage to nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties. In fact, the utility of topical and even systemic local anesthetics for the treatment of different neuropathic pain conditions (such as postherpetic neuralgia) likely reflects their action on sodium channels that accumulate in injured nerve fibers.
Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and electrophysiological distinct laminae (Basbaum and Jessell, 2000) (Figure 1). For example, Aδnociceptors project to lamina I as well as to deeper dorsal horn (lamina V). The low threshold, rapidly conducting Aβ afferents, which respond to light touch, project to deep laminae (III, IV, and V). By contrast, C nociceptors project more superficially to laminae I and II.Connections between Primary Afferent Fibers and the Spinal CordThere is a very precise laminar organization of the dorsal horn of the spinal cord; subsets of primary afferent fibers target spinal neurons within discrete laminae. The unmyelinated, peptidergic C (red) and myelinatedAδnociceptors (purple) terminate most superficially, synapsing upon large projection neurons (red) located in lamina I and interneurons (green) located in outer lamina II. The unmyelinated, nonpeptidergicnociceptors (blue) target interneurons (blue) in the inner part of lamina II. By contrast, innocuous input carried by myelinated Aβ fibers (orange) terminates on PKCγ expressing interneurons in the ventral half of the inner lamina II. A second set of projection neurons within lamina V (purple) receive convergent input from Aδ and Aβ fibers.The most ventral part of lamina II is characterized by the presence of excitatory interneurons that express the gamma isoform of protein kinase C (PKC), which has been implicated in injury-induced persistent pain (Malmberg et al., 1997). Recent studies indicate that this PKCγ layer is targeted predominantly by myelinatednonnociceptive afferents (Neumann et al., 2008). Consistent with these anatomical studies, electrophysiological analyses demonstrate that spinal cord neurons within lamina I are generally responsive to noxious stimulation (via Aδ and C fibers), neurons in laminae III and IV are primarily responsive to innocuous stimulation (via Aβ), and neurons in lamina V receive a convergent nonnoxious and noxious input via direct (monosynaptic) Aδ and Aβ inputs and indirect (polysynaptic) C fiber inputs. The latter are called wide dynamic range (WDR) neurons, in that they respond to a broad range of stimulus intensities. There is also commonly a visceral input to these WDR neurons, such that the resultant convergence of somatic and visceral inputs likely contributes to the phenomenon of referred pain, whereby pain secondary to an injury affecting a visceral tissue (for example, the heart in angina) is referred to a somatic structure (for example, the shoulder).
Glutamate/NMDA receptor-mediated sensitization. After intense stimulation or persistent injury, activated C and Aδ nociceptors release a variety of neurotransmitters, including glutamate, substance P, calcitonin-gene related peptide (CGRP), and ATP, onto output neurons in lamina I of the superficial dorsal horn (red). As a consequence, normally silent NMDA glutamate receptors located in the postsynaptic neuron can now signal, increase intracellular calcium, and activate a host of calcium-dependent signaling pathways and second messengers including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and Src. This cascade of events will increase the excitability of the output neuron and facilitate the transmission of pain messages to the brain.) Disinhibition. Under normal circumstances, inhibitory interneurons (blue) continuously release GABA and/or glycine (Gly) to decrease the excitability of lamina I output neurons and modulate pain transmission (inhibitory tone). However, in the setting of injury, this inhibition can be lost, resulting in hyperalgesia. Additionally, disinhibition can enable nonnociceptivemyelinated Aβ primary afferents to engage the pain transmission circuitry such that normally innocuous stimuli are now perceived as painful. This occurs, in part, through the disinhibition of excitatory PKCγ expressing interneurons in inner lamina II.Microglial activation. Peripheral nerve injury promotes release of ATP and the chemokine fractalkine that will stimulate microglial cells. In particular, activation of purinergicP2-R receptors, CX3CR1, and Toll-like receptors on microglia (purple) results in the release of brain-derived neurotrophic factor (BDNF), which through activation of TrkB receptors expressed by lamina I output neurons, promotes increased excitability and enhanced pain in response to both noxious and innocuous stimulation (that is, hyperalgesia and allodynia). Activated microglia also release a host of cytokines, such as tumor necrosis factor α (TNFα), interleukin-1β and 6 (IL-1β, IL-6), and other factors that contribute to central sensitization.
Projection neurons within laminae I and V constitute the major output from the dorsal horn to the brain (Basbaum and Jessell, 2000). These neurons are at the origin of multiple ascending pathways, including the spinothalamic and spinoreticulothalamic tracts, which carry pain messages to the thalamus and brainstem, respectively (Figure 2). The former is particularly relevant to the sensory-discriminative aspects of the pain experience (that is, where is the stimulus and how intense is it?), whereas the latter may be more relevant to poorly localized pains. More recently, attention has focused on spinal cord projections to the parabrachial region of the dorsolateral pons, because the output of this region provides for a very rapid connection with the amygdala, a region generally considered to process information relevant to the aversive properties of the pain experience.From these brainstem and thalamic loci, information reaches cortical structures. There is no single brain area essential for pain (Apkarian et al., 2005). Rather, pain results from activation of a distributed group of structures, some of which are more associated with the sensory-discriminative properties (such as the somatosensory cortex) and others with the emotional aspects (such as the anterior cingulate gyrus and insular cortex). More recently, imaging studies demonstrate activation of prefrontal cortical areas, as well as regions not generally associated with pain processing (such as the basal ganglia and cerebellum). Whether and to what extent activation of these regions is more related to the response of the individual to the stimulus, or to the perception of the pain is not clear. Finally, Figure 2 illustrates the powerful descending controls that influence (both positive and negatively) the transmission of pain messages at the level of the spinal cord.
Early binding studies and bioassays defined three main types of opioid receptors in the central nervous system, the mu-, delta- and kappa-receptors. Additional receptor types were proposed (e.g., sigma, epsilon, orphanin), but those are currently not considered “classical” opioid receptors (Kieffer and Gaveriaux-Ruff, 2002). T Opioid receptors belong to the family of seven transmembrane G-protein coupled receptors (GPCR) and show 50–70% homology between their genes (Evans et al., 1992, Kieffer et al., 1992, Meng et al., 1993 and Wang et al., 1993). Additional pharmacological subtypes may result from alternative splicing, posttranslational modifications, or receptor oligomerization. Opioid receptors are expressed by central and peripheral neurons, by neuroendocrine (pituitary, adrenals), immune, and ectodermal cells (Zöllner and Stein, 2007).
local application of conventional opioids in peripheral damaged tissue, a new generation of opioid drugs unable to pass the blood–brain barrier is emerging, avoiding the unwanted, centrally mediated effects mentioned above (Brower, 2000, Riviere, 2004 and Stein et al., 2003). Moreover, peripheral endogenous mechanisms counteracting pain and inflammation have been discovered. Such effects are produced by interactions between opioid peptides and opioid receptors located on peripheral endings of primary afferent neurons, by anti-inflammatory cytokines, and/or by endocannabinoids (Rittner et al., 2008 and Stein et al., 2003). Endogenous opioid peptides that can act at peripheral opioid receptors have been identified within skin and subcutaneous tissues, particularly in inflammatory cells. This has led to new directions of research, for example, the selective targeting of opioid peptide-producing cells to sites of injury, the augmentation of opioid peptide synthesis by gene transfer, and the inhibition of inflammation by peripherally acting opioid drugs (Machelska, 2007, Rittner et al.,
There was no place in the specificity concept of the nervous system for ‘plasticity,’ in which neuronal and synaptic functions are capable of being molded or shaped so that they influence subsequent perceptual experiences. Plasticity related to pain represents persistent functional changes, or ‘somatic memories,’29–31 produced in the nervous system by injuries or other pathological events. The recognition that such changes can occur is essential to understanding chronic pain syndromes, such as low back pain and phantom limb pain that often destroy the lives of the people who suffer them.
Pains that do not conform to present-day anatomical and neurophysiological knowledge are often attributed to psychological dysfunction. This view of the role of psychological generation in pain persists to this day notwithstanding evidence to the contrary. Psychopathology has been proposed to underlie phantom limb pain,25 dyspareunia,59 orofacialpain,60 and a host of others including pelvic pain, abdominal pain, chest pain and headache.61 However, the complexity of the pain transmission circuitry described in the previous sections means that many pains that defy our current understanding will ultimately be explained without having to resort to a psychopathological etiology. Pain that is ‘nonanatomical’ in distribution, spread of pain to non-injured territory, pain that is said to be out of proportion to the degree of injury, and pain in the absence of injury have all, at one time or another, been used as evidence to support the idea that psychological disturbance underlies the pain. Yet each of these features of supposed psychopathology can now be explained by neurophysiological mechanisms that involve an interplay between peripheral and central neural activityTaken together, these novel mechanisms that explain some of the most puzzling pain symptoms must keep us mindful that emotional distress and psychological disturbance in our patients are not at the root of the pain. In fact, more often than not, prolonged pain is the cause of distress, anxiety, and depression. This is not to say that psychological and emotion distress do not contribute to pain nor that pain cannot be caused by thoughts and feelings even in psychologically healthy people. But strange and unusual pains should not be taken as a proxy for psychopathology. Attributing pain to a psychological disturbance is damaging to the patient and provider alike; it poisons the patient-provider relationship by introducing an element of mutual distrust and implicit (and at times, explicit) blame. It is devastating to the patient who feels at fault, disbelieved and alone.
We are so accustomed to considering pain as a purely sensory phenomenon that we have ignored the obvious fact that injury does not merely produce pain; it also disrupts the brain's homeostatic regulation systems, thereby producing. By recognizing the role of the stress system in pain processes, we discover that the scope of the puzzle of pain is vastly expanded and new pieces of the puzzle provide valuable clues in our quest to understand chronic painThe disruption of homeostasis by injury activates programs of neural, hormonal, and behavioral activity aimed at a return to homeostasis. The particular programs that are activated are selected from a genetically determined repertoire of programs and are influenced by the extent and severity of the injury. When injury occurs, sensory information rapidly alerts the brain and begins the complex sequence of events to re-establish homeostasis. Cytokines are released within seconds after injury. These substances, such as gamma-interferon, interleukins 1 and 6, and tumor necrosis factor, enter the bloodstream within 1–4 min and travel to the brain. The cytokines, therefore, are able to activate fibers that send messages to the brain and, concurrently, to breach the blood–brain barrier at specific sites and have an immediate effect on hypothalamic cells. The cytokines together with evaluative information from the brain rapidly begin a sequence of activities aimed at the release and utilization of glucose for necessary actions, such as removal of debris, the repair of tissues, and (sometimes) fever to destroy bacteria and other foreign substances. Following severe injury, the noradrenergic system is activated: epinephrine is released into the blood stream and the powerful locus coeruleus/norepinephrine system in the brainstem projects information upward throughout the brain and downward through the descending efferent sympathetic nervous system. Thus, the whole sympathetic system is activated to produce readiness of the heart, blood vessels, and other viscera for complex programs to reinstate homeostasis.
Recent advances in our understanding of the mechanisms that underlie pathological pain have important implications for the treatment of both acute and chronic pain. Since it has been established that intense noxious stimulation produces a sensitization of CNS neurons, it is possible to direct treatments not only at the site of peripheral tissue damage, but also at the site of central changes (see review by Coderre at al.45). Furthermore, it may be possible in some instances to prevent the development of central sensitization which contributes to pathological pain states. The evidence that acute post-operative pain intensity and/or the amount of pain medication patients require after surgery are reduced by perioperative administration of variety of agents via the epidural46–48 or systemic route49–51 suggests that the surgically-induced afferent injury barrage arriving within the CNS, and the central sensitization it induces, can be prevented or at least obtundedsignificantly.52,53 The reduction in acute pain intensity associated with preoperative epidural anesthesia may even translate into reduced pain54 and pain disability55 weeks after patients have left the hospital and returned home.
We have traveled a long way from the concept that seeks a simple one-to-one relationship between injury and pain. We now have a theoretical framework in which a genetically determined template for the body-self is modulated by the powerful stress system and the cognitive functions of the brain, in addition to the traditional sensory inputs. The neuromatrix theory of pain—which places genetic contributions and the neural-hormonal mechanisms of stress on a level of equal importance with the neural mechanisms of sensory transmission—has important implications for research and therapy. In the last few years our knowledge on pharmacology of pain has evolved significantly. The discoveries in the field of neurobiology, pharmacology and genetics of pain at different levels like systemic, synaptic, cellular and molecular helped to identify new mechanisms and research in this area provided novel targets for novel drugs and treatment of pain diseases.
An immediate recommendation is that interdisciplinary pain clinics should expand to include specialists in endocrinology and immunology. Such a collaboration may lead to insights and new research strategies that may reveal the underlying mechanisms of chronic pain and give rise to new therapies to relieve the tragedy of unrelenting suffering associated with needless pain
