TRPV1 Unlike TRPV2 Is Restricted to a Subset of Mechanically Insensitive Cutaneous Nociceptors Responding to Heat

Abstract

In the present study, a murine ex-vivo somatosensory system preparation was used to determine the response characteristics of cutaneous sensory neurons staining positively for TRPV1 or TRPV2. TRPV1 immunostaining was found exclusively (11/11) in a specific set of mechanically insensitive unmyelinated (C) nociceptors that responded to heating of their receptive fields. No cutaneous Cfibers that responded to both mechanical and heat stimuli stained positively for TRPV1 (0/62). The relationship between TRPV2 and heat transduction characteristics was not as clear, as few unmyelinated or myelinated fibers that responded to heat contained TRPV2. TRPV2 was found most frequently in mechanically sensitive myelinated fibers, including both low threshold and high threshold mechanoreceptors (nociceptors). While TRPV2 was found in only 1 of 6 myelinated polymodal nociceptors, it was found in a majority (10/16) of myelinated mechanical nociceptors. Thus, while the in vivo role of TRPV1 as a heat sensitive channel in cutaneous sensory neurons is clearly defined, the role of TRPV2 in cutaneous neurons remains unknown. These results also suggest that TRPV1 may be essential for heat transduction in a specific subset of mechanically insensitive cutaneous nociceptors, and that this subset may constitute a discrete heat input pathway for inflammation-induced thermal pain.Perspective-The distinct subset of murine cutaneous nociceptors containing TRPV1 has many attributes in common with mechanically insensitive C-fibers in humans that are believed to play a role in pathological pain states. Therefore these murine fibers provide a clinically relevant animal model for further study of this group of cutaneous nociceptors.

Nociceptors: the sensors of the pain pathway

“…Furthermore, noxious acute heat responses evoked in rat C-MH saphenous fibers were not decreased by ruthenium red at concentrations that block the capsaicin response (45). In humans, the prolonged time course of the strong C-H response to capsaicin applied to the receptive field matched the duration of the perceived pain (60) and is consistent with the results of rodent studies (50). Disparities regarding the contribution of TRPV1 to fiber subtype functionality (especially C-MH fibers) may depend on species, stimulation techniques, tissue preparation, and sensitivity of the assay.…”

“…Cultures of rodent sensory ganglia indicate expression of TRPV1 in approximately 50% of neurons (61) and 75% of small-medium diameter neurons (43), similar to the proportion of C-MH fibers in a skin-nerve-sensory ganglion-spinal cord preparation (49). Although functionally characterized mouse C-MH neurons were not immunoreactive for TRPV1 (50), neurons with low expression levels may have been missed. Importantly, every identified mouse C-H neuron (~10% of the population) revealed TRPV1-like immunoreactivity (50) and no functionally identified C-H nociceptors were observed in TRPV1-deficient animals.…”

“…Importantly, every identified mouse C-H neuron (~10% of the population) revealed TRPV1-like immunoreactivity (50) and no functionally identified C-H nociceptors were observed in TRPV1-deficient animals. This result cannot be explained by a phenotypic switch to C-MH fibers in these mice since mechanical sensitivity of the C-fiber population was unchanged (50). Furthermore, noxious acute heat responses evoked in rat C-MH saphenous fibers were not decreased by ruthenium red at concentrations that block the capsaicin response (45).…”

“…Although functionally characterized mouse C-MH neurons were not immunoreactive for TRPV1 (50), neurons with low expression levels may have been missed. Importantly, every identified mouse C-H neuron (~10% of the population) revealed TRPV1-like immunoreactivity (50) and no functionally identified C-H nociceptors were observed in TRPV1-deficient animals. This result cannot be explained by a phenotypic switch to C-MH fibers in these mice since mechanical sensitivity of the C-fiber population was unchanged (50).…”

“…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.…”