This document discusses the anatomy and physiology of pain. It defines pain and describes its sensory and emotional components. It outlines the neurobiology of pain, including transduction, transmission, modulation, and perception. It discusses nociceptors, sensitization, and the gate control theory of pain. It describes the peripheral and central nervous system pathways involved in pain, including the dorsal horn, ascending pathways, descending modulation, and supraspinal regions. It also discusses complex regional pain syndromes.

1. ANATOMY OF PAIN
PATHWAY
MODERATOR : Dr. GURJEET KHURANA
PRESENTER : Dr. DEEPTI

2. DEFINITION
• Pain is an unpleasant sensory and emotional experience associated
with actual or potential tissue damage.

3. COMPONANETS
Sensory-discriminative : results in the perception of the quality of pain (pricking,
burning, aching), the location of the painful stimulus, and the intensity of the pain.
Motivational-affective : responses to painful stimuli include attention and arousal,
somatic and autonomic reflexes, endocrine responses, and emotional changes

4. NEUROBIOLOGY OF PAIN
• Pain involves a series of complex neurophysiologic processes, collectively termed
nociception.
• Four distinct components:
1. transduction
2. transmission
3. modulation
4. perception

5. 1.Transduction : is the process by which a noxious stimulus (e.g., heat,
cold, mechanical
distortion) is converted to an electrical impulse in sensory nerve endings.
2.Transmission : is the conduction of these electrical impulses to the CNS
with the major connections for these nerves - dorsal horn of the spinal cord
- thalamus with projections to cingulate,
insular,
and somatosensory cortices.

6. 3.Modulation : Process of altering pain transmission. It is likely that both inhibitory
and excitatory mechanisms modulate pain (nociceptive) impulse transmission in
the PNS and CNS.
4.Pain perception : it is mediated through the thalamus acting as the central relay
station for incoming pain signals and the primary somatosensory cortex serving for
discrimination of specific sensory experiences.

8. Pain may occur in the absence of the occurrence of these four steps :
• Pain from trigeminal neuralgia occurs in the absence of transduction of a
chemical stimulus at a nociceptor.
• Modulation of pain impulses may not occur if specific nervous system tracts are
injured. For example, phantom limb pain occurs in the absence of nociception or
nociceptors (pain receptors).

9. PERIPHERAL NERVE PHYSIOLOGY
Nociceptors (Pain Receptors)
• Nociceptors are a specialized class of primary afferents that respond to intense,
noxious stimuli in skin, muscles,joints, viscera, and vasculature.
• In normal tissues, nociceptors are inactive until they are stimulated by sufficient
energy to reach the stimulus (resting) threshold.
• Thus, nociceptors prevent random signal propagation(screening function) to the
CNS for the interpretation of pain.

10. NOCICEPTORS
“C” fibers : Unmyelinated, conduction velocity < 2m/sec .
Carry signal from burning pain from intense heat stimuli.
Sustained pressure.
“A”fibers : Myelinated ,conduction velocity >2m/sec, 2types
1. Type I fibers : Includes Aβ and Aδ
These are high threshold mechanoreceptors respond to
heat, mechanical and chemical stimuli.Therefore referred as polymodal
nociceptors.

11. 2. Type II fibers : Aδ fibers , conduction velocity 15m/sec
Respond to first pain sensation from heat stimuli.
Thus pain sensation transduced by both myelinated and unmyelinated fibers

12. SENSITIZATION OF NOCICEPTORS
• Means increased responsiveness of peripheral neurons responsible for pain
transmission
• Sensitization of nociceptors is attributable to the release of inflammatory
mediators and adaptation of signaling pathways in primary sensory neurons
induced by noxious stimuli.
• In the majority of cases of acute inflammation, the process naturally resolves
as tissues heal and peripheral sensitization diminishes and nociceptors return to
their original resting threshold

13. • Chronic pain, however, occurs if the conditions associated with inflammation
does not resolve, resulting in sensitization of peripheral and central pain signaling
pathway
• That results in increased pain sensations to normally painful stimuli hyperalgesia
and the perception of pain sensations in response to normally nonpainful stimuli
allodynia.
• In primary sensory neurons may also undergo significant adaptation after noxious
stimuli, significantly lowering the firing thresholds of nociceptors and critically
contributing to the induction and maintenance of neuronal sensitization, which
manifest as allodynia and hyperalgesia.

14. CHEMICAL MEDIATERS
Bradykinin directly activate
Protons nociceptors and/or induce the
prostaglandinE2 response to painful stimuli
purines sensitization of the nociceptor.
Cytokines
serotonin, histamine
arachidonic acid metabolites activate the inflammatory cells
cytokines which in turn release
thereby leading to sensitization.

16. Primary Hyperalgesia and Secondary Hyperalgesia
Primary Hyperalgesia Secondary Hyperalgesia
Hyperalgesia at
the original site of injury
Hyperalgesia in the uninjured skin
surrounding the injury
characterized by the presence of
enhanced pain from heat and mechanical
stimuli
characterized by enhanced pain response
to only mechanical stimuli
Interaction between the
proinflammatory mediators and their
receptors in nociceptors leads to the
induction of primary hyperalgesia
sensitization of central neuronal circuits
processing nociceptive information may
account for the secondary hyperalgesia
after tissue injury.

17. Central Nervous System Physiology

18. Dorsal Horn: The Relay Center for Nociception
• Afferent fibers from peripheral nociceptors enter the spinal cord in the dorsal root
• ascend or descend several segments in the Lissauer tract
• synapse with the dorsal horn neurons for the primary integration of peripheral
nociceptive information.

19. • The dorsal horn contains four major neuronal components:
1. The central terminals of primary afferent axons
2. Intrinsic neurons which terminate locally or extend into other spinal segment
3. Projection neurons that pass rostrally in the white matter to reach various parts
of the brain
4. Descending axons that extend caudally from several brain regions and
terminate in the dorsal horn where they play an important role in modulating the
integration of nociceptive information.

20. The central terminals of primary afferents occupy highly ordered spatial locations
in the dorsal horn.
The dorsal horn consists of six laminae :
• Laminae I (marginal layer) : projection and interneurons
• Laminae II (substantia gelatinosa) : interneurons
primary regions where afferent C fibers synapse on second order neuron.
• LaminaeV : site of second-order wide dynamic range (WDR) and nociceptive-
specific (NS) neurons that receive input from nociceptive and nonnociceptive
neurons.

23. • Myelinated fibers innervating muscles and viscera terminate in laminae I, IV to
VII,and the ventral horn.
• Unmyelinated fibers from these organs terminate in laminae I, II,andV as well as
X.
• Interneurons have axons that remain in the same lamina as the cell body, and
they also give rise to axons that extend into other laminae.
• Interneurons in the dorsal horn can be divided into two main functional types:
Inhibitory cells : use GABA and/or glycine as their principal transmitter.
Excitatory cells : glutamatergic.

24. • Projection neurons with axons that project to the brain are present in relatively
large numbers in lamina I and are scattered through the deeper part of the dorsal
horn (laminae III toVI) and the ventral horn.
• lamina I and the laminae III and IV projection neurons that express the NK1
receptor are heavily innervated by substance P–containing primary afferents.
• Those in laminaI, together with some of the projection cells in deeper laminae,
have axons that cross the midline and ascend to a variety of supraspinal targets
including the thalamus, the midbrain PAG, lateral parabrachial area of the pons,
and various parts of the medullary reticular formation

25. • Two types of descending monoaminergic (serotoninergic and norepinephrinergic)
axons project from the brain throughout the dorsal horn
• Terminating in laminae I and II, and are involved in descending pain modulation.
• Serotoninergic axons in the spinal cord originate in the medullary raphe nuclei
• Norepinephrine are derived from cells in the locus ceruleus and adjacent areas of
the pons.

26. GATE THEORY
• The gate control theory of pain was first proposed by Ronald Melzack and Patrick
Wall in 1965.
• It illustrate the neuronal network underlying pain modulation (a
neurologic“gate”) in the spinal dorsal horn.
• painful information is projected to the supraspinal brain regions if the gate is
open, whereas painful stimulus is not felt if the gate is closed by the simultaneous
inhibitory impulses
• Rubbing the skin of painful area seems to somehow relieve the pain associated
with a bumped elbow.

27. • In this case, rubbing the skin activates large-diameter myelinated afferents
(Ab), which are “faster” than Ad fibers or C fibers conveying painful
information.
• These Ab fibers deliver information about pressure and touch to the dorsal
horn and override some of the pain messages (“closes the gate”) carried by
the Ad and C fibers by activating the inhibitory interneurons in the dorsal
horn.
• This hypothesis provided a practical theoretical basis for some approaches
such as massage, transcutaneous nerve stimulation, and acupuncture to
effectively treat pain in clinical patients.

29. Ascending Pathway for Pain Transmission
The major ascending pathways important for pain include :
1. The spinothalamic tract
2. Spinomedullary
3. Spinobulbar projections
4. Spinohypothalamic tract (hypothalamus and ventral forebrain).
5. Some indirect projections, such as the dorsal column system and the
spinocervicothalamic pathway, also exist to forward nociceptive information to
the forebrain through the brainstem.
6. Pathways originating from the medulla trigeminal sensory nuclei also exist to
process the nociceptive information from the facial structures.

30. • STT is the most closely associated with pain, temperature, and itch sensation
• STT originate in the spinal dorsal horn neurons in lamina I (receiving input from
small-diameter Ad and C primary afferent fibers)
• laminae IV andV (receiving input primarily from large-diameter Ab fibers from
skin),
• laminaeVII andVIII (receiving convergent input from large-diameter skin and
muscle, joint inputs).
• 85% to 90% of neuronal cells with projections extending through the STT are
found on the contralateral side, with 10% to 15% on the ipsilateral side.

31. • The lateral STT originates predominantly from lamina I cells.
• The anterior STT originates from deeper laminaeV andVII cells.
• In the lateral STT, the axons from caudal body regions tend to be located more
laterally (i.e., superficially) in the white matter, whereas those from rostral body
regions are located more medially (closer to midline).
• The axons of STT terminate in several distinct regions of the thalamus.

34. • Spinobulbar projections originate from similar neurons as those in the STT (i.e.,
laminae I,V, andVII in the spinal dorsal horn).
• Spinal projections to the medulla are bilateral.
• Those to the pons and mesencephalon have a contralateral dominance.
• Spinobulbar projections terminate mainly in four major areas of the brainstem,
including the regions of catecholamine cell groups (A1–A7), the parabrachial
nucleus, PAG, and the brainstem reticular formation.

35. • The spinohypothalamic tract (SHT) originates bilaterally from cells in laminae I,V,
VII, and X over the entire length of the spinal cord.
• The SHT axons often have connections with the contralateral diencephalon
• Decussate in the optic chiasm, and then descend ipsilaterally through the
hypothalamus and as far as the brainstem.
• The SHT appears to be important for autonomic, neuroendocrine,and emotional
aspects of pain.

36. Supraspinal Modulation of Nociception
• The most commonly activated regions during acute and chronic pain include
SI, SII, anterior cingulate cortex (ACC), insular cortex (IC), prefrontal cortex,
thalamus, and cerebellum.
• These brain regions form a cortical and subcortical network, which are critically
involved in the formation of emotional aspects of pain and the central modulation
of pain perception.

37. • Somatosensory cortices (e.g., SI and SII) are more important for the perception of
sensory features(e.g., the location and intensity of pain)
• Limbic and paralimbic regions (e.g., ACC and IC) are more important for the
emotional and motivational aspects of pain.
• Anesthetized humans, without conscious awareness of pain, still exhibit
significant pain-evoked cerebellar activation, suggesting that pain-evoked
cerebellar activity may be more important in regulation of afferent nociceptive
activity than in the perception of pain.

39. Descending Pathways of Pain Modulation
• descending pathways originating from certain supraspinal regions may
concurrently promote and suppress nociceptive transmission through the dorsal
horn, termed
Descending inhibition pathway (DI)
Descending facilitation pathway (DF).
• The PAG and the RVM regions of the brainstem as the critical brain regions
underlying descending pain modulation

40. • PAG neurons receive direct or indirect inputs from the amygdala, nucleus
accumbens , hypothalamus and others, with ascending nociceptive afferents
from the dorsal horn.
• The RVM receives input from serotonin-containing neurons of the dorsal raphe
and neurotensinergic neurons of the PAG
• Spinally projecting noradrenergic neurons of the pontine tegmentum contribute
significantly to pain modulation.
• Electrical stimulation in each of these regions produces behavioral analgesia and
inhibition of dorsal horn neurons mediated by spinal a2-adrenergic receptors.

41. • There are parallel inhibitory and facilitatory output pathways from the RVM
to spinal cord.
• There are three distinct populations of neurons in the RVM:
those that discharge beginning just prior to the occurrence of withdrawal from
noxious heat (on cells)
those that stop firing just prior to a withdrawal reflex (off cells), and those that
show no consistent changes in activity when withdrawal reflexes occur(neutral
cells)

42. • Off cells exert a net inhibitory effect on nociception
• On cells exert a net facilitatory effect on nociception.
• Neutral cells are serotonergic neurons, and projections of neutral cells tonically
release serotonin at the level of the dorsal horn and modulate the action of other
descending pain modulation systems via 5-HT3 receptor.12

43. • The PAG–RVM system serves as one of the major brain sites underlying opiate
induced analgesia.
• In the RVM, µ opioid receptors are primarily located on the on cells, and κ opioid
receptor in the off cells.
• The µ opioid receptor agonists, including morphine and other opioid analgesics,
produce a direct postsynaptic hyperpolarization by an increased K+ conductance
in RVM on cells.
• These agents also act presynaptically to depress GABAergic synaptic
transmission.

44. • Activation of k opioid receptors exhibits bidirectional pain modulation, either
analgesia or antagonism of µ opioid receptor–mediated analgesia.
• Chronic exposure to opiates induces emergence of functional δ opioid receptors
in PAG–RVM system, which exhibit δ opioid receptor–mediated analgesia.

45. Complex Regional Pain Syndromes
• The International Association for the Study of Pain (IASP) Classification of Chronic
Pain defines complex regional pain syndrome (CRPS) as
“a variety of painful conditions following injury which appears regionally having a
distal predominance of abnormal fi dings, exceeding in both magnitude and
duration the expected clinical course of the inciting event often resulting in
significant impairment of motor function, and showing variable progression over
time.”

47. • Two types of CRPS :
• Type I (reflex sympathetic dystrophy) and type II (causalgia) by the presence of a
major identifiable nerve injury in the CRPS II and the absence of a major nerve
injury in CRPS I.
• CRPS I develops more often than CRPS II, and females are more
often affected than males.

48. The following IASP clinical criteria are applied to diagnose the CRPS.
1. type I is a syndrome that develops after an initiating noxious event
2. Spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory
of a single peripheral nerve, and is disproportionate to the inciting event
3. there is or has been evidence of edema, skin blood flow abnormality, or
abnormal sudomotor activity in the region of the pain since the inciting event
4. this diagnosis is excluded by the existence of conditions that would otherwise
account for the degree of pain and dysfunction

49. CRPS type II:
1. type II is a syndrome that develops after nerve injury; spontaneouspain or
allodynia/hyperalgesia occurs and is not necessarily limited to the territory
of the injured nerve
2. there is or has been evidence of edema, skin blood flow abnormality, or
abnormal sudomotor activity in the region of the pain since the inciting
event
3. this diagnosis is excluded by the existence of conditions that would
otherwise account for the degree of pain and dysfunction

51. Pain in Neonate and Infant
• the human fetus develops pain perception by 23 weeks of gestation.
• Postnatal maturity of pain behavior develops quickly after birth.
• newborns and young children have significantly lower pain thresholds and
exaggerated pain responses compared to adults.
• Some clinical studies reveal the long-term effects of neonatal pain experience,
which is affected by several confounding factors such as
• gestational age at birth,length of intensive care stay,intensity of the stimulus and
parenting style.
• Toddlers and adolescents exhibit long-lasting hypersensitivity to painful stimuli
after painful experiences as neonates.
• These observations highlight the clinical importance of optimal management of
pain in neonates and infants.