Temperature information is transmitted by primary sensory neurons propagating action potentials from the periphery to the central nervous system, where multiple thermosensory inputs are integrated to drive appropriate behavioral or physiological outputs. Certain aspects of thermosensation are intrinsic to sensory neurons themselves as shown by temperature-evoked currents in isolated sensory neurons, or existence of temperature-sensitive ion channels in sensory neurons. TRPV1, which was originally discovered as a capsaicin receptor, is expressed in a subset of small diameter sensory neurons, and activated by heat exceeding 42°C. TRPV2, a homologue of TRPV1, can be activated by noxious heat over 52°C, and expressed in medium to large diameter neurons. These characteristics of TRPV2 closely resemble type I A-fiber nociceptors, leading to the hypothesis that TRPV2 is a heat transducer in these nociceptors.
In order to investigate the physiological role of TRPV2 in detection of noxious heat, I generated TRPV2 knockout mice, and examined their nociceptive behaviors as described in chapter 1. Unlike initial expectation, TRPV2 knockout mice exhibited normal thermal sensitivity under uninjured or skin-sensitizing conditions of tissue inflammation or neuropathy. Their sensitivity to punctuate mechanical stimuli was unaltered as well. The phenotype of TRPV2 knockout mice was not affected by the presence of TRPV1 or signaling in the TRPV1-positive afferents. These results suggest that TRPV2 has other functions than a primary sensor of noxious heat in sensory neurons.
In the brain, TRPV2 expression is enriched in the suprachiasmatic nucleus. In chapter 2, I examined the circadian behaviors of TRPV2 knockout mice. Light entrainment or development of food anticipatory activity under restricted feeding was normal in TRPV2 knockout mice. In constant darkness, TRPV2 knockout mice exhibited delayed phase advance in core body temperature oscillation, whereas phase advance of wheel-running activity was normal. Inconsistent results from these two parameters may be explained either by non-photic entrainment effect of wheels, or selective deficits of temperature oscillation in TRPV2 knockout mice.
In chapter 3, I present findings of TRPV2 upregulation in regenerating peripheral axons. Prominent TRPV2 immunofluorescence in a longitudinal form was observed in the distal portion of the crushed sciatic nerve, which was absent in the distal stumps of the transected sciatic time devoid of regrowing axons. In the spinal cord, motor neurons and central projections of sensory neurons with damaged axons by sciatic nerve crush also increased TRPV2 level. Further studies need to be conducted to clarify the role of TRPV2 in nerve regeneration.
|Advisor:||Caterina, Michael J.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 69/04, Dissertation Abstracts International|
|Keywords:||Nociception, TRPV2, Thermosensation|
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