In this ppt I mentioned all the imp point related to pain pathway and pain pathophysiology. refrence: essentials of interventional techniques in managing chronic pain (laxmaiah manchikanti)

1. PAIN PATHOPHYSIOLOGY AND
MECHANISMS
Dr Minhaj Akhter
Post-Doctoral Fellowship SR
Pain and Palliative Care
Department of Anaesthesiology and Critical Care
AIIMS, Jodhpur
27/10/2021

2. Definition of Pain
• “An unpleasant sensory and emotional experience associated
with actual or potential tissue damage or described in terms of
such damage” (IASP)
• Derived from Latin -“Poena” meaning
punishment from God

4. • Neuropathic pain is unique in that it bypasses the first step of
converting a stimulus to an electrical impulse, as the stimulus
involves direct injury to the nerve
• Identification of the mechanisms of pain is critically important
for effective management, as it informs treatment decisions at
every step
• Peripheral nervous system (PNS) is the site for transduction
and transmission, while the central nervous system (CNS) is
where modulation (i.e., transformation) and perception occur

5. Classification of pain

7. Key Terminology
• Nociceptor: Sensory nerve receptor that responds to noxious
stimuli
• Polymodal nociceptor: Specialized neurons that respond to
chemical, mechanical, and heat stimuli and promote
neurogenic inflammation by neuropeptide release
• Spontaneous discharge: Action potentials that are generated
without exogenous stimulation
• Allodynia: Characterized by pain in response to a non-painful
stimulus

8. • Hyperalgesia: Characterized by an increased pain sensation to
painful stimulus
• Noxious stimulus: A stimulus that causes tissue injury or
threatens to cause tissue injury
• Peripheral sensitization: Process by which the threshold for an
action potential is lowered
• First pain: Sharp and prickling pain that is generated by
activation of rapidly conducting Aδ fibers
• Second pain: Dull and burning pain that results from
activation of slowly conducting C fibers

9. Transduction
Nociceptors
• It is a neuronal receptor that
senses noxious stimuli
• Sensitive to three types of
injurious stimuli – mechanical,
thermal, and chemical
• Continuously communicating
with immune, inflammatory,
vascular, and local cells to
respond to any changes in tissue
chemistry, extracellular matrix,
and other neuronal, endocrine, or
systemic byproducts

10. • Voltage-gated ion channels, ligand-gated ion channels, and
ligand-mediated second messenger mechanisms facilitate
detection of the noxious stimuli
• Voltage-gated ion channels allow the
influx of sodium and calcium ions,
and generate an action potential that
will relay the pain signal more
proximally in the nervous system
• After propagation of the impulse, an
efflux of potassium ions through the
channels enables the neurons to
repolarize to their resting state
Voltage gated
sodium channel

11. • Ligand-gated ion channel receptors function by activating ion
channels or second messenger systems
• Several receptor types have been identified on nociceptors for
specific ligands
a) Tissue breakdown products such as protons, adenosine triphosphate (ATP), or
bradykinin
b) Inflammatory mediators such as leukotriene B4 and prostaglandin E2;
c) Exogenous chemicals such as capsaicin and vanilloids;
d) Excitatory agents such as glutamate, aspartate, norepinephrine, and ATP
e) Inhibitory agents such as γ-aminobutyric acid (GABA) and opioid peptides
f) Sensitizing agents such as IL-1β, IL-6, and other cytokines, histamine,
serotonin, and nerve growth factor (NGF)
g) Desensitizing agents such as leukocyte inhibitory factor, interferon-γ, and
opioid peptides

12. • Once activated by the ligand,
second messenger systems act
via phospholipase-linked or
adenylate cyclase-linked
receptors to open ion channels
within the cell membrane and
initiate an action potential
• Second messengers include
cAMP, cGMP, calcium ions,
diacylglycerol (DAG), inositol
triphosphate(IP3), arachidonic
acid metabolites, and nitric
oxide

13. Transmission
• Three primary nerve classes involved in pain transmission: Aß,
Aδ, and C afferent nerves

14. Aß fibers
• Principally involved in the conduction of nonnociceptive
input, such as vibration, movement, or light touch
• They are large myelinated fibers with a rapid conduction
velocity (35 m–75 m per second)
• These fibres also recruit inhibitory interneurones in the
substantia gelatinosa of the dorsal horn, which inhibits
nociceptive input at the same spinal segment
• This mechanism is one of the fundamental components of the
gate control theory, whereby an innocuous stimulus will
reduce the nociceptive input from the same region

17. Aδ fibers
• Relatively large myelinated fibers with slower conduction
velocity than the Aß fibers, but faster (5 m–30 m per second)
than the C fibers
• Two types
1. Mechano-nociceptors respond preferentially to intense
and potentially harmful mechanical stimulation
2. Polymodal Aδ fibers respond to mechanical, thermal, and
chemical stimulation.
• Because of the rapid conduction velocity, the Aδ fibers are
responsible for the first pain sensation, a rapid pinprick, sharp,
and transient sensation

18. C fibers
• Because of their small caliber and lack of myelin, the
conduction of the C fibers is relatively slow (0.5m–2 m per
second)
• They represent three quarters of the sensory afferent input and
are mostly recruited by nociceptive stimulation
• However, they are also involved in non-nociceptive
somatosensory information, such as in the sensation of
pruritus, and paradoxically, in the perception of pleasant touch

19. Modulation
Peripheral Mechanisms
• First modulation events that occurs in the PNS
• Sensitization is defined as a hyperexcitable state designed to
protect the body from continued harm at the site of original
tissue injury
• Persistently elevated stimulus level causes the release of free
fatty acids which further form PGE-2 and PGI-2 which
activate the adenylate cyclase pathway, generating an
increased production of cAMP

20. • After phosphorylation cAMP depolarize of the injured and
adjacent uninjured peripheral nerves at lower action potential
thresholds, causing sensitization
• Several other mediators, such as calcitonin gene-related peptide
and substance P, increase vascular membrane permeability,
thereby releasing more active byproducts including
prostaglandins, bradykinin, growth factors, and cytokines,
which further sensitize nociceptors
• Numerous mediators and byproducts involved, peripheral
sensitization is difficult to treat pharmacologically

21. Spontaneous pain
• Occur at dorsal root ganglion or anywhere distally along the
injured peripheral nerve from ectopic discharges
• Due increased expression of sodium and calcium channel
(alpha-2-delta) the dorsal root ganglion or within a neuroma at
the site of injury
• Gabapentin and Pregabalin act on this channel alpha-2-delta
subunit causing decreased release of glutamate into the
synapse, thus limiting the transmission of chronic pain signals

22. • Expression of mu opioid receptors (MOR) in the dorsal root
ganglia decreased in patients with neuropathic pain so
requiring higher doses of opioids to attain pain relief
• Conversely, inflammation has been shown to increase the
quantity and affinity for opioids of mu receptors in the dorsal
root ganglion

23. Central Spinal Mechanisms
• The dorsal horn and spinal trigeminal nucleus are the principal
sites for pain modulation in the central nervous system
• Under normal conditions,
nociceptive afferents synapse in the
dorsal horn if the signal originates
from the body and spinal trigeminal
nucleus if the stimulus originates in
the face
• Light touch stimuli are processed by
dorsal column nuclei and the chief
sensory nucleus of the trigeminal
nerve for the body and face,
respectively

24. • Within the dorsal horn, larger afferent signals synapse in
deeper layers of the dorsal horn, while signals from smaller
nociceptors end in superficial layers

25. • Layers of the dorsal horn are histologically identified as ten
Rexed laminae,
• Where lamina I refers to the most superficial layer and lamina
X refers to the central canal

26. • Most superficial layers of the dorsal horn, including the
marginal layer (lamina I) and substantia gelatinosa (lamina II),
are the primary synaptic sites for nociceptive Aδ and C afferent
nerves, with primary afferent nociceptive signals frequently
terminating in lamina V as well

27. • Two important second-order neurons are found in the dorsal
horn: nociceptive-specific (NS) and wide dynamic range
neurons (WDR)
• NS neurons are present in the superficial layers of the dorsal
horn, these neurons respond to Aδ and C polymodal afferents
and have a high threshold for activation
• WDR neurons are embedded deeper within the dorsal horn,
predominantly at lamina V, and respond to a variety of both
painful and innocuous afferent signals, including nociceptive,
visceral, and sympathetic

28. • Due to their ability to receive input from diverse neuronal
fibers, they are responsible for viscerosomatic convergence,
which is the phenomenon whereby visceral pain can be
concurrently sensed in a somatic dermatome
• One classic example of this is ischemic cardiac pain felt
radiating into the left arm

29. Spatial Convergence
• WDR neurons can also contribute to a widening of the area of
neuropathic pain
• Nerve damage at a specific dermatome can cause sensitization
of the WDR, which can then erroneously interpret adjacent
innocuous dermatomal afferent signals as being noxious
• This phenomenon is observed when a herniated disc at one
level may result in the spontaneous firing of dorsal root ganglia
at adjacent levels, which may partially explain why some
targeted interventional treatments fail to alleviate symptoms
• There are several other neuronal elements and cellular
mediators with the CNS, such as inhibitory interneurons, glial
cells, and cytokines, whose alteration in normal function can
result in pathological pain

30. • Inhibitory interneurons lie within the dorsal horn of the spinal
cord serve as an intermediary between afferent neurons and
NS or WDR neurons
• They normally function to attenuate the strength of the afferent
signal prior to synapsing with the NS or WDR neuron by
releasing inhibitory neurotransmitters, namely, GABA,
glycine, and endogenous opioids
• In neuropathic pain states, nerve injury can result in
dysfunctional GABA production causing cellular changes that
lead to apoptosis of the inhibitory interneurons, ultimately
resulting in mechanical hyperalgesia

31. • Another important element in pain modulation within the
central nervous system is glial cells, comprising 70% of all
cells within the system
• Glial cells include astrocytes, microglia, satellite cells, and
Schwann cells
• These cells undergo a phenotypic switch in response to nerve
injury that contributes to the development of chronic pain

32. • Microglia and astrocytes become activated via the mitogen-
associated protein kinase (MAPK) pathway within hours of
nerve injury and release a host of mediators including
prostaglandins, excitatory amino acids, cytokines, chemokines,
nitric oxide, and free radicals that sensitize surrounding
nociceptive neurons, this leads to an upregulation of glutamate
and glucocorticoid receptors, inducing a state of spinal
excitation
• Pharmacological interventions aimed at these excitatory
pathways, including those that target inflammatory cytokines
such as tumor necrosis factor-alpha and interleukins (IL-1β and
IL-6), have been shown to attenuate neuropathic, inflammatory,
and cancer pain, making glial cells an attractive target in pain
research

33. • Due to changes in normal functioning of dorsal horn neurons,
lowered response thresholds, ectopic discharge, and expanded
receptive fields can result in patients experiencing the
phenomena of hyperalgesia and/or allodynia
• Multiple mechanisms leading to this phenomenon have been
described including windup and heterosynaptic central
sensitization

34. Windup and heterosynaptic central sensitization
• Windup is caused by hyperactive WDR neurons that in essence
become “wound-up” after prolonged exposure to bombarding
afferent discharges
• Continual nociceptive firing causes
a release of several
neuromodulators including
glutamate, substance P, and
calcitonin gene-related peptide that
activate NMDA receptors, thereby
altering WDR neurons in such a
way that they exhibit
inappropriately exaggerated
responses to either innocuous or
noxious stimulus

35. • Classic heterosynaptic central sensitization is a result of
intense nociceptive stimuli that cause WDR neuronal
thresholds to be lowered, such that a patient experiences pain
even after the initial stimulus has subsided
• Given the role of the NMDA receptor in the pathophysiology
of “windup” and other neural mechanisms that contribute to
persistent pain, researchers have extensively studied this
receptor to examine its potential as a therapeutic target
• Therapies that target this receptor, including high-dose
ketamine infusions and the use of oral NMDA receptor
antagonists, including dextromethorphan, amantadine, and
memantine

36. Central Supraspinal Mechanisms
• After processing in periphery, nociceptive signal continues its
path to the brain via ascending spinal tracts
• Mostly from spinothalamic tract, which originates from
laminae I, IV, V, and VII in the dorsal horn
• Trigeminothalamic tracts from laminae I and V supplying
sensory input from the head

37. • These fibers ascend toward the
thalamus terminating along the
way in numerous locations
including the ventrolateral
medulla, locus coeruleus,
parabrachial nucleus,
periaqueductal gray, and reticular
formation
• These terminations further
communicate in a complex web
like system with the anterior
cingulate cortex, insular cortex,
prefrontal cortex, amygdala,
hippocampus, and limbic system

38. Periaqueductal gray-rostral ventromedial medulla (PAG-RVM)
system
• Descending spinal pathway in pain
modulation
• Three types of cells: “on,” “off,”
and “neutral” present in RVM
system
• The role of the first two types is to
either promote or inhibit pain
transmission, respectively, while
the role of “neutral” cells has yet to
be conclusively ascertained

39. • The PAG, through the production of endogenous opioids, can
modulate these cells both directly and indirectly
• Opioids inhibit “on” cells that become active in the presence
of nociceptive inputs
• In the absence of pain stimuli, activated “off” cells
predominate
• Thus, modulation of pain in the supraspinal region can be
excitatory or inhibitory

40. • The predominant sites of supraspinal modulation are the
brainstem, diencephalon, and the cerebral cortex that connects
with both the ascending and descending spinal pathways
• Repeated neuropathic pain transmission can cause neuroplastic
changes that increase excitability to the noxious stimuli
• Conversely, intact inhibitory pathways can modulate the pain
signal by attenuating it or preventing further transmission to
the brain

42. Perception
• Perception is the final step in the pain pathway and is
influenced by the context, cognitive factors, and emotions
• Origin of competing inhibitory and facilitatory descending
signals involved in modulation often arises from similar
regions within the CNS
• These modulatory regions, including the locus coeruleus,
anterior cingulate gyrus, amygdala, and hypothalamus,
communicate through the medulla and/or periaqueductal gray
to the spinal cord

43. • The main neurotransmitters involved in these transmissions
are norepinephrine, dopamine, endogenous opioids, and
serotonin
• They also play a role in anxiety, depression, and insomnia,
which help explain the high co-prevalence rate between sleep
disorders, anxiety and mood disorders, and chronic pain and
why medications that are effective for one condition are often
useful for others
• Predominance of either inhibitory or facilitatory descending
signals is directed by the clinical context of pain, including
emotions and expectations that’s why positive expectations
have been shown to result in better treatment outcomes

44. • Reorganization of cortical neurotransmitters occurs after
injury, and the extent of the change correlates positively with
the subjective intensity and duration of the pain as well as
anxiety levels
• Other changes that occur in the brain of chronic pain patients
include aberrant corticotropin-releasing factor signals in the
limbic system, a brain center associated with emotion
processing, and an overall loss of gray matter; the latter has
been shown to be reversible to some extent with appropriate
pain management

45. • Collectively, these changes in the normal structure and
function of the brain may have profound implications for
cognition in chronic pain patients
• Patients with chronic pain have a significant impairment in
making decisions, maintaining attention, and recalling
memories

46. Conclusion
• The pathway of pain is composed of four parts, transduction,
transmission, modulation, and perception, which each step is
characterized by unique cellular mechanisms that enable the
nociceptive signal to continue onward or eventually stop
• By understanding these underlying mechanisms and
continuing to study the cellular processes that are incompletely
understood, scientists are better equipped to create therapies
that focus on a specific mechanism that has become
maladaptive, leading to pathological pain

47. • Although this mechanistic overlap likely conferred an
evolutionary advantage to our forebears, it now presents
unique challenges to effective treatment
• Clinical therapies are also limited by their side effect profiles,
additionally complicating available treatment modalities
• Although it remains a formidable challenge, it is critical for
researchers and healthcare providers to understand how all
four parts of the pain pathways interact so that modalities can
be designed and implemented to prevent and treat the various
pain conditions

48. Thank
you