Nociceptive primary afferents: they have a mind of their own

Abstract

Nociceptive primary afferents have three surprising properties: they are highly complex in their expression of neurotransmitters and receptors and most probably participate in autocrine and paracrine interactions; they are capable of exerting tonic and activity-dependent inhibitory control over incoming nociceptive input; they can generate signals in the form of dorsal root reflexes that are transmitted antidromically out to the periphery and these signals can result in neurogenic inflammation in the innervated tissue. Thus, nociceptive primary afferents are highly complicated structures, capable of modifying input before it is ever transmitted to the central nervous system and capable of altering the tissue they innervate.

Figure 1. Immunostained nociceptive primary afferents visualized as they penetrate the epidermis

Modified from Zylka et al. , with permission.

Figure 2. Schematic drawing of two nociceptors with their terminals expanded at the level of the skin

The dorsal root ganglia (DRG) and central processes of these fibres (terminating in the spinal cord dorsal horn) are also sketched. Nociceptors express a large variety of receptors and channels and they contain numerous ligands, many of which they release. Receptor activation in the periphery occurs through volume transmission. This allows for autocrine (1) and paracrine (2) regulation of their activity. Ligands with non-neural sources are also listed. 5HT, serotonin; ACh, acetylcholine, ATP, adenosine triphosphate, Angio II, angiotensin II; Bomb, bombesin; BK, bradykinin; CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; HA, histamine; iGluR, ionotropic glutamate receptor; mGluR, metabotropic glutamate receptors; mrgprd, MAS-related G protein-coupled receptor; NK1, neurokinin 1; NPY, neuropeptide Y; PGE, prostaglandin E; SP, substance P; TRPs, transient receptor potential receptors; TRKs, tyrosine kinase receptors. (Reproduced from Carlton & Coggeshall, , with permission.)

Figure 3. Behavioural data demonstrating group II/III involvement in activity-dependent inhibition of TRPV1 receptors

Intraplantar capsaicin (CAP) alone results in flinching (A and B) and Lift/Lick (C and D) behaviour. This behaviour is enhanced when CAP is injected with LY341495 (LY), a group II/III antagonist. CAP in one hindpaw and LY in the other results in behaviour that is no different from CAP alone, confirming that LY does not become systemic but is having a local effect. (Reproduced from Carlton et al. , with permission.)

Figure 4. Producing primary afferent depolarization (PAD) in central terminals of sensory fibres

The proposed circuitry underlying dorsal root reflex activity at the level of the primary afferent in the dorsal horn is shown. An axoaxonic contact is made by a GABAergic interneuron onto a primary afferent terminal. Release of GABA from the interneuron and activation of GABA_A receptors produces an efflux of Cl^– from the primary afferent terminal, resulting in its depolarization. The Cl^– is concentrated in the primary afferent terminal by the Na⁺,K⁺,Cl^– cotransporter symbolized by the dark oval in the membrane of the afferent. (Modified from Alvarez-Leefmans et al. , with permission.)

Figure 5. Evidence of DRR activity in fibres in the median nerve following a T10 spinal cord injury

A, dorsal root reflex (DRR) activity is recorded from the proximal stump of the cut median nerve in vivo. B, trace of spontaneous DRRs and evoked DRRs (produced by mechanical stimulation of the forepaw) recorded from the median nerve proximal stump.

Figure 6. Evidence that DRR activity increases in spinal cord-injured (SCI) animals compared to naive and sham

Histograms show the increased percentage of C (A) and Aδ (B) fibres exhibiting DRR activity in spinal cord-injured rats compared to naive and sham. *P < 0.05 compared to naive; †P < 0.05 compared to sham, one-way ANOVA.