Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses

Abstract

Vanilloid receptor 1 (TRPV1) has been proposed to be the principal heat-responsive channel for nociceptive neurons. The skin of both rat and mouse receives major projections from primary sensory afferents that bind the plant lectin isolectin B4 (IB4). The majority of IB4-positive neurons are known to be heat-responsive nociceptors. Previous studies suggested that, unlike rat, mouse IB4-positive cutaneous afferents did not express TRPV1 immunoreactivity. Here, multiple antisera were used to confirm that mouse and rat have different distributions of TRPV1 and that TRPV1 immunoreactivity is absent in heat-sensitive nociceptors. Intracellular recording in TRPV1 Ϫ/Ϫ mice was then used to confirm that TRPV1 was not required for detecting noxious heat. TRPV1 Ϫ/Ϫ mice had more heatsensitive neurons, and these neurons had normal temperature thresholds and response properties. Moreover, in TRPV1 Ϫ/Ϫ mice, 82% of heat-responsive neurons did not express immunoreactivity for TRPV2, another putative noxious heat channel.

Nociceptors: the sensors of the pain pathway

“…This suggests that, at least in mice, heat sensors other than TRPV1 are the major contributors to acute heat-induced pain. 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.…”

“…Although human C-MH polymodal nociceptors are activated in a temperature range (39°C-51°C) similar to recombinant TRPV1 (58) and have been reported to be transiently activated by capsaicin (60), genetic deletion of TRPV1 in mice only partially reduces noxious heat sensitivity in behavioral assays (42,43) and has no effect on heat responsiveness of the C-fibers tested (42,44,49). This suggests that, at least in mice, heat sensors other than TRPV1 are the major contributors to acute heat-induced pain.…”

“…TRPV2 (Table 3) has been suggested to mediate, at least in part, the receptor potential in A-MH type Ifibers, since it is activated by temperatures greater than 52°C in recombinant expression studies (62); however, the lack of selective pharmacological tools for manipulation of TRPV2 activity has hindered rigorous evaluation of this hypothesis. Transducers of heat stimuli into the noxious range other than TRPV1 and TRPV2 (45,49) include other TRPV channels (TRPV3 and TRPV4) that have been reported to exist on sensory neurons (10) as well as constitutively active K + channels (KCNK2) inhibited by heat (63) ( Table 3). Although TRPV3 undergoes dramatic sensitization to repeated heat stimuli, TRPV3 does not appear to be involved in agonist sensitization of C-fiber heat responses (44).…”

“…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.…”

“…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.…”