An overview of pathways encoding nociception

Abstract

The nervous system detects and interprets a variety of chemical, mechanical, and thermal stimuli. In the face of tissue injury, local inflammatory products perpetuate ongoing activity and sensitisation of the peripheral nerve termini. This ongoing activity evokes a state of robust spinal facilitation mediated by a number of local circuits, the net effect yielding an enhanced message of nociception to higher centres. This messaging typically wanes with the resolution of inflammation or wound healing. However, there are situations in which peripheral and central components of the pain transmission pathway extend and enhance the pain state, leading to a persistent hypersensitivity, e.g., an acute to chronic pain transition. Current work points to the contribution of innate and adaptive immunity in creating these enduring conditions. We briefly describe the underlying biological components of both physiological pain processing and pathological pain processing, as well as the acute to chronic pain transition and the role of innate and adaptive immunity in this transition.

Figure 1:

A. Tissue injury, inflammation, or infection lead to local release of pro-inflammatory mediators (inflammatory soup) from resident cells (mast cells, Schwann cells), in migrating cells (macrophages, neutrophils), damaged cells, and blood vessels. These products act on receptors expressed on the afferent C fiber terminal to mediate an ongoing terminal depolarization and increased intracellular Ca⁺⁺, which, in turn, activates terminal kinases. Phosphorylation of terminal receptors and channels enhances their responsiveness and results in “terminal sensitization”. B. Nociceptive afferents synapse onto superficial (Lamina 1) and deep (Lamina V) neurons, and, though activation of afferent terminal CaVs, release glutamate and peptides (substance P) which act on eponymous post-synaptic receptors. In the face of ongoing C fiber input, the second order neuron displays marked increases in excitability resulting from increased intracellular Ca⁺⁺ that activates a myriad of protein kinases which i) phosphorylate receptors and channels, and ii) activate a variety of excitatory enzyme systems and iii) enhancing gene transcription. Other facilitatory components of dorsal horn function activated by ongoing C fiber input are: i) activation of glia (microglia and astrocytes) which release a constellation of pro-inflammatory molecules, ii) reduced effects of local GABA and glycinergic inhibition and iii) bulbospinal facilitatory input. C. These events initiate and maintain a hyperexcitable state, sending the processed nociceptive signals to higher brain centers though the contralateral spinothalamic tract to the thalamus, and collateral projections into brainstem nuclei. Supraspinal projections largely follow two major trajectories: those projecting into the lateral (somatosensory) thalamus and thence to the somatosensory cortex and those projecting to more medial regions that then project to areas such as the inferior insula and the anterior cingulate. Other details considered in this figure are presented in the text. Abbreviations: 5-HT, serotonin; A2, adenosine receptor; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; BK 1/2, bradykinin receptor; CaV, voltage-gated calcium channel; CGRP, calcitonin gene related peptide; CGRP, calcitonin gene related peptide; COX, cyclooxygenase ; CP-AMPA, calcium permeable AMPA receptor; EP, prostaglandin receptor; FPR1, formyl peptide receptor 1; GABA, gamma-aminobutyric acid; Gs, stimulatory signaling protein.; H1, histamine receptor; IL-1, Interleukin-1; IL-1b, Interleukin-1; LC, locus coeruleus; LPS, lipopolysaccharide; MAPK, mitogen activated protein kinase; NA, noradrenalin; NaV, voltage-gated sodium channel; NGF, nerve growth factor; NK1, neurokinin 1 receptor; NMDA, N-methyl-D-aspartate receptor; P2X3, purinoreceptor 3; PAR, proteinase activated receptor; PGE2, prostaglandin E2; PKA, protein kinase A; PKC, protein kinase C ; PLA2, phospholipase A2; sP, substance P; TLR4, Tropomyosin receptor kinase A; VMPO, ventromedial pars oralis; VR1, vanilloid receptor type 1.