Nociceptors: the sensors of the pain pathway

Alt om nociceptorer og smerte. Nevner at nedstigende signaler i ryggmargen sender signaler ut i perferien hvor nervetråden utløser betennelser og dermed gir smerte i huden.

Since enhanced excitability of primary sensory neurons in inflammatory and pathologic pain states is a major contributor to the perception of pain, specific pharmacological agents that specifically dampen aberrant activity are desirable in the design of pain therapeutics.

Anatomy of nociceptors.

(A) Somatosensory neurons are located in peripheral ganglia (trigeminal and dorsal root ganglia) located alongside the spinal column and medulla. Afferent neurons project centrally to the brainstem (Vc) and dorsal horn of the spinal cord and peripherally to the skin and other organs. Vc, trigeminal brainstem sensory subnucleus caudalis. (B) Most nociceptors are unmyelinated with small diameter axons (C-fibers, red). Their peripheral afferent innervates the skin (dermis and/or epidermis) and central process projects to superficial laminae I and II of the dorsal horn. (C) A-fiber nociceptors are myelinated and usually have conduction velocities in the Aδ range (red). A-fiber nociceptors project to superficial laminae I and V.

Pain, as a submodality of somatic sensation, has been defined as a “complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and manifested by certain autonomic, psychological, and behavioral reactions” (1).

Normally, nociception (see Glossary, Sidebar 1) and the perception of pain are evoked only at pressures and temperatures extreme enough to potentially injure tissues and by toxic molecules and inflammatory mediators.

Pain is described as having different qualities and temporal features depending on the modality and locality of the stimulus, respectively: first pain is described as lancinating, stabbing, or pricking; second pain is more pervasive and includes burning, throbbing, cramping, and aching and recruits sustained affective components with descriptors such as “sickening” (3).

As opposed to the relatively more objective nature of other senses, pain is highly individual and subjective (4, 5) and the translation of nociception into pain perception can be curtailed by stress or exacerbated by anticipation (6).

Adequate stimuli include temperature extremes (> ~40°C–45°C or < ~15°C), intense pressure, and chemicals signaling potential or actual tissue damage. Nociceptors are generally electrically silent (12) and transmit all-or-none action potentials only when stimulated.

However, nociceptor activity does not per se lead to the perception of pain. The latter requires peripheral information to reach higher centers and normally depends on the frequency of action potentials in primary afferents, temporal summation of pre- and postsynaptic signals, and central influences (7).

Most nociceptors have small diameter unmyelinated axons (C-fibers) (12) bundled in fascicles surrounded by Schwann cells and support conduction velocities of 0.4–1.4 m/s (22) (Figure ​(Figure1).1). Initial fast-onset pain is mediated by A-fiber nociceptors whose axons are myelinated and support conduction velocities of approximately 5–30 m/s (most in the slower Aδ range) (22).

Noxious stimuli are transduced into electrical signals in free “unencapsulated” nerve endings that have branched from the main axon and terminate in the wall of arterioles and surrounding connective tissue, and may innervate distinct regions in the dermis and epidermis (17, 30). The endings are ensheathed by Schwann cells except at the end bulb and at mitochondria- and vesicle-rich varicosities (17). A–fibers lose their myelin sheath and the unmyelinated A-fiber branches cluster in separated small spots within a small area, the anatomical substrate for their receptive field (17). C-fiber branches are generally more broadly distributed, precluding precise localization of the stimulus (17).

In contrast, specialized nonneuronal structures conferring high sensitivity to light touch, stretch, vibration, and hair movement are innervated by low threshold A-fibers (11).

They terminate predominantly in laminae I, II, and V of the dorsal horn on relay neurons and local interneurons important for signal modification (13, 37, 38) (Figure ​(Figure1,1, B and C). The relay neurons project to the medulla, mesencephalon, and thalamus, which in turn project to somatosensory and anterior cingulate cortices to drive sensory-discriminative and affective-cognitive aspects of pain, respectively (38). Local inhibitory and excitatory interneurons in the dorsal horn as well as descending inhibitory and facilitatory pathways originating in the brain modulate the transmission of nociceptive signals, thus contributing to the prioritization of pain perception relative to other competing behavioral needs and homeostatic demands (39).

Whereas heat- and chemical-induced nociceptor responses correlate with pain perception in humans (9,24), mechanical stimulation of C-MH (24) and rapidly adapting A-HTM (18) fibers may not (24) (Tables​(Tables11 and ​and2).2).

To this end, an understanding of species-specific differences is critical, as exemplified by the dramatically different phenotypes in mice and humans lacking Nav1.7: although mice lacking Nav1.7 show a mechanosensory (pinch) and formalin-induced (5%) pain phenotype (103), humans lacking Nav1.7 are insensitive to pain altogether (104).

Anterograde transmission of action potentials from the spinal cord to the periphery results in release of peptides and other inflammatory mediators in the skin and exacerbates nociceptor excitability and pain (see below). It is at the spinal level that nonnociceptive neurons are recruited by strong nociceptor activation through functional modulation of local circuits (105).

Injury to the skin induces protective physiological responses aimed at decreasing the likelihood of exacerbating the injury. After an injury induced by pungent chemicals (e.g., capsaicin, mustard oil) and burn, stimulation of the injured area produces enhanced pain to noxious stimuli (primary mechanical and thermal hyperalgesia) dependent on C-fiber activity that manifests as a decrease in threshold to activate C-MH fibers and to perceive pain (9, 19, 106). Immediately surrounding the injured area, a zone of flare (reddening) develops and stimulation of even a larger secondary zone produces pain in response to normally innocuous stimuli (e.g., brush stroke) (secondary mechanical allodynia) as well as enhanced responsiveness to noxious mechanical (secondary mechanical hyperalgesia) and thermal (heat) hyperalgesia if spatial summation is invoked (secondary thermal hyperalgesia) (21, 105, 107). Here, noxious punctate stimulation of C-nociceptors induces secondary mechanical hyperalgesia mediated by A-nociceptors (7) and innocuous dynamic mechanical stimuli (gentle stroking) provokes nonnociceptor A-fiber–mediated pain (108). Cellular mechanisms underlying this complicated response involve both peripheral and central processes (14, 38, 105, 107) and require nociceptor input, particularly A-MH and C-MH fibers (19, 91, 105). After a burn, A-MH fibers (most likely type I) mediate primary heat hyperalgesia in glabrous skin (9).

Centrally propagating impulses can antidromically invade peripheral arborizations innervating other areas in the afferent’s receptive field (axon reflex), causing the release of peptides (e.g., substance P, CGRP, somatostatin) and/or other bioactive substances from the terminal (e.g., cytokines) into the interstitial tissue (17). The released substances produce a myriad of autocrine or paracrine effects on endothelial, epithelial, and resident immune cells (Langerhans), which lead to arteriolar vasodilatation (“flare,” via CGRP) and/or increased vascular permeability and plasma extravasation from venules (edema, via substance P). Liberated enzymes (e.g., kallikreins) and blood cells (e.g., platelets, mast cells) further contribute to the accumulation of inflammatory mediators and neurogenic inflammation (110, 111).

A recently described phenomenon (“hyperalgesic priming”) evoked by cytokine- and neurotrophin-induced recruitment of Gi/o-PKCε signaling in nociceptors can produce prolonged sensitization and mechanical hyperalgesia and may contribute to chronic pain (114).

Significant crosstalk between these pathways exists at multiple levels including stimulus transduction (118), peripheral terminals during neurogenic inflammation, and central connections during central sensitization and may underlie paradoxical temperature sensation.

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