The talk based on this article was delivered, under the same heading, by Dr.
Palanisamy Vijayanand at the Indian Association of Palliative Care (IAPC) National Conference at Bhubaneshwar, February 2014. The article was published by the IAPC in the book ‘Concepts of Palliative Care,’ as a compendium of selected articles.
In the past, pain was considered to be a response to nociceptive stimuli like injury or inflammation in the periphery. Now, it is known that pain is not just biological, but has psychological and social determinants to it.
The International Association for the Study of Pain has defined pain as ‘…an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’.
Perception of pain and its threshold are the result of complex interactions between sensory, emotional, and behavioral factors. It is influenced by past experience/ memory, meaning of the situation, attention/ distraction, feeling of control, power of suggestion/ placebo. Inflammation and nerve injury can reduce pain thresholds and increase sensitivity to sensory stimuli. Conversely, ‘battlefield analgesia’, in which soldiers receive severe injuries with little immediate awareness of pain is a situation in which thresholds can increase.
Acute pain has a protective function and its experience may lead to future avoidance of potentially harmful situations and possible injury. However, chronic pain which persists beyond healing of injury serves no protective or restorative purpose; indeed, some consider the pain to be a disease in itself. The talk would focus on changes in the peripheral nervous system, spinal cord, and higher centers, initiated by a variety of noxious insults, the persistence of which transforms acute pain into chronic pain.
Free nerve endings, mainly the slow conducting, unmyelinated C fibers (90%) and fast conducting thinly myelinated A delta fibers (10%) act as nociceptors 1, 2. These nociceptor afferents terminate in dorsal horn of spinal cord and medulla. Unmyelinated C fiber nociceptors terminate principally in lamina II (the substantia gelatinosa) 3. Some unmyelinated fibers also ascend and descend several segments in Lissauer’s tract before terminating on neurons that project to higher centers. Small myelinated Aδ nociceptors terminate principally in the superficial dorsal horn (lamina I) and deeper in lamina V 1, 3. There is a polysynaptic, intraspinal pathway that connects primary afferents to motor neuron which is a basic pathway that underlies the withdrawal reflex 1. Nociceptive fibers cross over and ascend in the anterolateral funiculus comprising the spinothalamic, spinoreticular, spinomesencephalic and spinolimbic tracts to terminate in the thalamus 3. En route, collaterals of the projection neurons activate multiple higher centers, including the nucleus reticularis and gigantocellularis. Neurons project from here to the thalamus, and also activate the nucleus raphe magnus and periaqueductal gray (PAG) of the midbrain. The descending fibers from the PAG, in turn, project to the nucleus raphe magnus and adjacent reticular formation 2. These neurons activate descending inhibitory neurons and travel via the dorsolateral funiculus to terminate in laminae I, II and IV of the dorsal horn of the spinal cord 1, 2, 3.
Peripheral pain mechanisms:
Peripheral sensitization :
After injury, inflammatory cells such as macrophages, lymphocytes, and mast cells and the peripheral terminals of nociceptive afferent fibers release compounds such as substance P, neurokinin A, and Calcitonin gene-related peptide (CGRP) as a part of a neurogenic inflammatory response 2. These peptides modify the excitability of sensory and sympathetic nerve fibers, induce vasodilatation and extravasation of plasma proteins, and promote the release of further chemical mediators by inflammatory cells 1, 2. These interactions result in a ‘soup’ of inflammatory mediators, including K+ and H+, serotonin, bradykinin, substance P, histamine, cytokines, nitric oxide, and products from the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism. These chemicals then act to sensitize high-threshold nociceptors such that low-intensity non noxious mechanical stimuli shall be now perceived as painful. There is also an increased responsiveness to thermal stimuli at the site of injury. This zone of ‘primary hyperalgesia’ surrounding the site of injury is a consequence of phenomenon of peripheral sensitization and is commonly observed following surgery and other forms of trauma 1, 2, 3.
Role of nerve growth factor in peripheral sensitization
Inflammation via the cytokines IL-1and TNF- alpha is associated with increased Nerve Growth Factor (NGF) expression. NGF plays a central role in peripheral sensitization mediated by both direct and indirect actions of inflammatory mediators on nociceptive afferents via Tyrosine kinase receptor 2. Furthermore, growth factors may mediate upregulation of various types of Na+ channel contributing to the features of spontaneous pain 3.
Silent nociceptors are found in joint capsules and walls of viscera. They are inactive under normal circumstances. However they get sensitized following inflammation/ injury leading to vigorous discharges contributing to hyperalgesia and allodynia 1, 2.
Peripheral nerve injury
- Peripheral nerve transaction interrupts retrograde axonal transport of growth factors. Sprouting of proximal neuronal stumps produces neuromata expressing altered Na+ channel isoforms capable of spontaneous firing; similar changes occur in the DRG 2.
- Sympathetic innervation and activation of DRG neurons leading to sympathetic mediated pain 2.
- Aβ fibers within laminae III and IV of the dorsal horn sprout and potentially form synaptic contact with nociceptive projection neurons of lamina II. Nonnociceptive (Aβ) afferent input may therefore activate nociceptive pathways, resulting in allodynia 1, 2, 3.
- Altered neuropeptide expression and loss of GABAergic inhibition within the dorsal horn may result in spontaneous activity of dorsal horn projection neurons 1, 2.
Neurotransmission within the dorsal horn encompasses excitatory transmitters released from the central terminals of primary afferent nociceptor and between neurons of the spinal cord; and inhibitory transmitters released by interneurons within the spinal cord and from supraspinal sources.
Glutamate is the main CNS excitatory neurotransmitter and plays a major role in nociceptive transmission in the dorsal horn 2. Glutamate acts at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, N-methyl-D-aspartate (NMDA) receptors, kainate (KA), and metabotropic glutamate receptors 2, 3. Repeated afferent input via Aδ and C fibers causes prolonged release of glutamate resulting in sustained activation of AMPA 2. This in turn primes the NMDA receptor with depolarization of the membrane to –30 mV, which enables Mg2+ to leave the channel and Ca2+ to enter the neurons 2, 3. Influx of Ca2+ into the neuron activates a number of pathways involving second messengers, including inositol trisphosphate (IP3), cGMP, eicosanoid, nitric oxide (NO), and protein kinase C 1, 3. NO acts in conjunction with presynaptic NMDA receptors, as a positive feedback mechanism, to up regulate afferent input further, and thereby potentiate nociceptive input 1, 3. Activation of NMDA receptors at pre- and postsynaptic loci initiates processes that contribute to the medium- or long-term changes observed in chronic pain states, including central sensitization, ‘wind up’ i.e increased gain of subsequent afferent input transmission, changes in peripheral receptive fields, induction of gene transcription, and long-term potentiation (LTP) which serves as memory at spinal level 1, 2, 3.
Modulation at a spinal level
The gate control theory
Large-diameter A delta afferents primarily activates inhibitory cells, and therefore reduces output from transmission neurons. Noxious input along small-diameter C fiber afferents primarily inhibits the inhibitory cells, and therefore increases the output from transmission cells. Faster conducting A delta fibers supersede noxious input from C fibers modulating pain perception. A further level of modulation in the gate theory is that descending pathways from the brain can also act to inhibit transmission of information by transmission cells 1, 2, 3. This pain transmission modulation by inhibitory spinal mechanisms via a balance between modulatory afferents and descending pathways was coined ‘gate theory’ by Melzack and Wall in 1965.
Both GABAergic and glycinergic interneurons are involved in tonic inhibition of nociceptive input; downregulation or loss of these neurons can result in features of neuropathic pain such as allodynia 2. While GABA-A receptor-mediated inhibition occurs through largely postsynaptic mechanisms, GABA-B mechanisms may be preferentially involved in presynaptic inhibition by suppressing excitatory amino acid release from primary afferent terminals 2, 3.
The PAG receives projections from the amygdala, frontal and insular cortex, and hypothalamus, and acts in concert with the rostral ventromedial medulla (RVM) to provide a descending pain modulatory system 2. Even though descending inhibition is activated by external stimuli, it is also tonically active and maintains a resting level of inhibitory function. Analgesia obtained from the lateral PAG is nonopioid in nature, whereas opioid analgesia is obtained from stimulation of the medial PAG. Inhibition may occur presynaptically by modulation of transmitter release, or postsynaptically by either excitation of local inhibitory interneurons or direct inhibition of second-order projection neurons 1, 2.
Opioids, Serotonin, Noradrenaline mainly and acetylcholine, GABA, thyrotropin-releasing hormone and somatostatin are the neurotransmitters involved in descending inhibition.
Opioid receptors modulate nociceptive input at supraspinal and spinal sites of analgesia. Supraspinally, there is a high density of opioid receptors in the PAG, nucleus raphe magnus, and locus ceruleus. Opioids act at a spinal level in the dorsal horn by activating presynaptic opioid receptors, which inhibit glutamate and neurokinin release from primary afferent terminals, and postsynaptic receptors, which inhibit second-order neuron depolarization 1, 2, 3. Serotonin is contained in a high proportion of nucleus raphe magnus cells and in terminals of descending fibers in the dorsal horn 2. Descending projections from the locus ceruleus act via Norepinephrine 2.
Thus ongoing activation of peripheral nociceptors with or without the presence of inflammatory mediators results in sustained peripheral sensitization supplemented by central sensitization and neuronal plasticity to result in manifestations of chronic pain. The talk would, in addition, focus briefly on the mechanisms of bone pain.
2) Physiology of pain. Michael J Hudspith, Philip J Siddall, and Rajesh Munglani. Foundations of Anesthesia (Second Edition), Basic Sciences for Clinical Practice. Eds: Hugh C Hemmings, Philip M Hopkins ISBN: 978-0-323-03707-5
3) Neurobiology of pain. Siddall PJ, Cousins MJ.; International Anesthesiology Clinic. 1997 Spring; 35(2):1-26.
Image Courtesy Mr. Balasubramanian Mariappan – Chitti Photography