Nociceptors: the sensors of the pain pathway (original) (raw)
Significant insights into the cellular and molecular basis of cutaneous nociception have been realized from studies on conscious humans and surrogate animal models (15, 16), although we are far from understanding the cell biology of pain perception. Advances are hampered by the difficulties inherent in studying neuronal processes in humans, cellular changes in nociceptors induced by invasive methods, the inability to record directly from the tiny structures where transduction of noxious stimuli occurs, and the uncertainty in model systems that an animal’s behavior is due to its perception of pain (15, 17). Although the morphology of sensory nociceptive nerve endings is highly conserved in animals from rodents to humans (5, 9, 17–19), cutaneous nociceptors are an extremely heterogeneous group of neurons housed in peripheral sensory ganglia located just outside the CNS that transduce external noxious stimuli in the skin, up to meters away from their cell bodies.
Minimally invasive extracellular single unit recordings from nerve fibers in peripheral nerves (microneurography) and skin-nerve preparations in mammals (20) and microneurography combined with psychophysical measurements in human subjects (15, 16, 21) have revealed the existence of distinct classes of nociceptor activated by noxious stimuli. 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).
The speed of transmission is directly correlated to the diameter of axons of sensory neurons and whether or not they are myelinated. 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 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). Nociceptive fibers have been classified (23) on the basis of their conduction velocity and sensitivity and threshold to noxious mechanical (M), heat (H), and cold (C) (Tables 1 and 2) (9, 23). Units responding to thermal, mechanical, and chemical stimuli (polymodal) are the most common C-fiber type observed in fiber recordings (C-MH, C-MC, C-MHC) (7, 9, 24) (Table 1). The expression of differential repertoires of transduction molecules (particularly chemical sensors) confers a rich functional heterogeneity upon this class. The use of electrical stimulation to search for receptive fields, rather than mechanical stimulation, identified nociceptors normally insensitive to mechanical and heat stimulation (silent; C-MiHi) that become sensitive to noxious mechanical or temperature only after being sensitized by inflammatory mediators (25, 26). C-fibers responsive to noxious heat (C-H; ~10% of C-nociceptors) play a major role in heat sensation (see below). A-fiber nociceptors are predominately heat- and or mechanosensitive (A-MH, A-H, A-M) (19, 27) (Table 2); however, sensitivity to noxious cold is also observed (27–29). Determining the contribution of each of these fiber types to pain perception requires an understanding of the molecular mechanisms underlying the detection of particular stimulus modalities and nociceptor connectivity in central circuits.
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.
Major heat and/or mechanosensitive nociceptor C-fiber classes
Major heat and/or mechanosensitive nociceptor A-fiber classes
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). Nociceptive endings are in the vicinity of keratinocytes, mast cells, and Langerhans cells, indicating the capacity of peripheral sensory endings to monitor the status of the skin (31). Nociceptors, like other primary somatosensory neurons, are pseudounipolar (Figure 1): a single process emanates from the cell body in the dorsal root ganglion (DRG) or trigeminal ganglion (TG) and bifurcates, sending a peripheral axon to innervate the skin and a central axon to synapse on second-order neurons in the dorsal horn of the spinal cord or the trigeminal subnucleus caudalis (Vc) (13), respectively (Figure 1A). In this way, propagating electrical signals between periphery and spinal cord (or brainstem) follow a direct axonal pathway, thus reducing the risk of conduction failure (32). Nociceptors are excitatory neurons and release glutamate as their primary neurotransmitter as well as other components including peptides (e.g., substance P, calcitonin gene-related peptide [CGRP], somatostatin) important in both central synaptic signaling and efferent signaling in the skin (13). Invasion of action potentials into the nociceptor soma via the short stem axon (32) can lead to biochemical changes (e.g., phosphorylation and activation of MAPK superfamily of signaling pathways) that ultimately alter gene expression and functional phenotype (33, 34). Although it is thought that direct communication between the soma of primary sensory neurons does not occur, vesicle exocytosis is observed in dissociated soma and may influence associated Schwann cells and possibly nearby neurons (35, 36). The central axon of DRG neurons enters the spinal cord via the dorsal root and sprouts branches that innervate multiple spinal segments in the rostral and caudal direction as well as the segment associated with the particular DRG and dorsal column nuclei of the caudal medulla (7). 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 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).
The cell body (soma) has served as an extremely useful model to study molecules and modulatory mechanisms mediating transduction of noxious stimuli, transmission of electrical signals to the CNS, and release of neurotransmitters and neuropeptides at central and peripheral terminals (40, 41). The soma expresses many molecular entities that are expressed in free nerve endings, central terminals, and axon (13). However, data from whole-cell soma recordings have been shown in a few cases to be at odds with behavioral or peripheral physiological data (e.g., heat transduction, refs. 42–44; and proton responsiveness, ref. 45). Although the underlying differences in these cases may be due to differential distribution of transduction molecules, it is also possible that nonneuronal peripheral components are required in vivo and lacking in dissociated neuronal cultures. This underscores the importance of corroborating results from cultured neurons with behavior and/or acute preparations retaining intact terminal fields. Labeling with retrograde dyes injected into the target tissue has enabled characterization of functional attributes of the soma of nociceptors innervating those tissues. The heterogeneity of functional phenotypes observed in isolated sensory cell bodies (46, 47) appears to reflect the variability observed in cutaneous nociceptor fiber types observed in studies in which recordings from fiber or soma during receptive field stimulation are combined with subsequent nociceptor labeling to identify terminal morphology (48, 49) and the expression of nocisensors (50), markers, and peptides (48) (Table 1). Nociceptors differentially express a variety of anatomical and biochemical markers (e.g., the expression of versican, the binding partner for the isolectin B4 [IB4]; ref. 51), however the functional significance of these markers, especially given striking species differences (49, 52), are unknown. Here, we will address how the functional heterogeneity of the nociceptor has an impact on the perception of pain.