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Heat Detection Without TRPV1
The Journal of Pain, Vol 9, No 7 (July), 2008: p 666 Available online at www.sciencedirect.com
Letter to the Editor Heat Detection Without TRPV1 To the Editor: In a recent editorial for The Journal of Pain, Dr. Herman Handwerker reviewed our paper on TRPV1 distribution in mouse cutaneous afferents and placed it within the context of the last 50 years of research on C-fibers. In our study, we found that for mouse afferents innervating hairy skin of the hind paw, TRPV1 immunolabeling was restricted to a small population of neurons (ca. 9%) that were mechanically insensitive, but responded to heat. These neurons were unique in that they exhibited extremely slow conduction velocity and fired at a much higher frequency to a heat ramp than did polymodal nociceptors that responded to both mechanical and heat stimuli.1 There were 2 major conclusions from our studies: (1) the predominant C-fiber type innervating hairy skin, polymodal nociceptors (referred to as C-mechanoheat fibers [CMH]), did not express TRPV1 and thus TRPV1 was not required for detection of heat stimuli, and (2) although a minority of cutaneous afferents, TRPV1-positive mechanically insensitive heat responsive fibers (CH) could play a significant role in the transmission of noxious heat stimuli. In his editorial, Dr. Handwerker cited a number of studies in which polymodal cutaneous afferents were shown to have capsaicin sensitivity (of which TRPV1 is the only known receptor), results that appear to be at odds with our studies. The cited experiments used various techniques to investigate this question but were invariably conducted on rats or humans. We do not believe that these experiments necessarily contradict our results. First, a number of labs including our own have shown that TRPV1 is more widely expressed in rat sensory neurons than in mouse (eg, Reference 2) and thus we would not be surprised if a portion of rat polymodal nociceptors exhibited capsaicin sensitivity.2 Second, none of the cited studies can conclusively determine whether the response to capsaicin by cutaneous polymodal nociceptors was direct or indirect. Dr. Handwerker suggests that one possible explanation for our results is that TRPV1 is expressed at levels that are below detection using immunohistochemical staining methods. Although we cannot rule out this possibility, it is impor-
666
tant to point out that we have also conducted the same experiments in TRPV1 knockout mice in the present study and previously3 and found that the heat-responsive properties of CMH fibers are normal. In contrast, CH cells cannot be found in TRPV1 knockout mice. These results speak to the most significant conclusion of our studies; there are at least 2 different mechanisms for detecting noxious heat stimuli: A TRPV1/TRPV2-independent mechanism(s) in CMH cells and a TRPV1-dependent mechanism in CH cells. Dr. Handwerker concludes by noting that in humans, CMH and CH fibers have been shown to have different biophysical properties exemplified by differential spike slowing after repetitive stimulation. Further, he states that if similar distinctions can be found for mouse CMH and CH afferents, this model system could be used to identify molecular difference that define these 2 populations of nociceptors. We are in complete agreement and would like to suggest that these populations could be used to identify alternative mechanisms that allow sensory neurons to detect heat that does not require TRPV1.
H. Richard Koerber, PhD Brian M. Davis, PhD Departments of Neurobiology and Medicine University of Pittsburgh Pittsburgh, Pennsylvania
References 1. Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR: TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298-308, 2008 2. Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M: GFR alpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci 13:2177-2182, 2001 3. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM: Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410-6415, 2004
Letter to the Editor Heat Detection Without TRPV1 To the Editor: In a recent editorial for The Journal of Pain, Dr. Herman Handwerker reviewed our paper on TRPV1 distribution in mouse cutaneous afferents and placed it within the context of the last 50 years of research on C-fibers. In our study, we found that for mouse afferents innervating hairy skin of the hind paw, TRPV1 immunolabeling was restricted to a small population of neurons (ca. 9%) that were mechanically insensitive, but responded to heat. These neurons were unique in that they exhibited extremely slow conduction velocity and fired at a much higher frequency to a heat ramp than did polymodal nociceptors that responded to both mechanical and heat stimuli.1 There were 2 major conclusions from our studies: (1) the predominant C-fiber type innervating hairy skin, polymodal nociceptors (referred to as C-mechanoheat fibers [CMH]), did not express TRPV1 and thus TRPV1 was not required for detection of heat stimuli, and (2) although a minority of cutaneous afferents, TRPV1-positive mechanically insensitive heat responsive fibers (CH) could play a significant role in the transmission of noxious heat stimuli. In his editorial, Dr. Handwerker cited a number of studies in which polymodal cutaneous afferents were shown to have capsaicin sensitivity (of which TRPV1 is the only known receptor), results that appear to be at odds with our studies. The cited experiments used various techniques to investigate this question but were invariably conducted on rats or humans. We do not believe that these experiments necessarily contradict our results. First, a number of labs including our own have shown that TRPV1 is more widely expressed in rat sensory neurons than in mouse (eg, Reference 2) and thus we would not be surprised if a portion of rat polymodal nociceptors exhibited capsaicin sensitivity.2 Second, none of the cited studies can conclusively determine whether the response to capsaicin by cutaneous polymodal nociceptors was direct or indirect. Dr. Handwerker suggests that one possible explanation for our results is that TRPV1 is expressed at levels that are below detection using immunohistochemical staining methods. Although we cannot rule out this possibility, it is impor-
666
tant to point out that we have also conducted the same experiments in TRPV1 knockout mice in the present study and previously3 and found that the heat-responsive properties of CMH fibers are normal. In contrast, CH cells cannot be found in TRPV1 knockout mice. These results speak to the most significant conclusion of our studies; there are at least 2 different mechanisms for detecting noxious heat stimuli: A TRPV1/TRPV2-independent mechanism(s) in CMH cells and a TRPV1-dependent mechanism in CH cells. Dr. Handwerker concludes by noting that in humans, CMH and CH fibers have been shown to have different biophysical properties exemplified by differential spike slowing after repetitive stimulation. Further, he states that if similar distinctions can be found for mouse CMH and CH afferents, this model system could be used to identify molecular difference that define these 2 populations of nociceptors. We are in complete agreement and would like to suggest that these populations could be used to identify alternative mechanisms that allow sensory neurons to detect heat that does not require TRPV1.
H. Richard Koerber, PhD Brian M. Davis, PhD Departments of Neurobiology and Medicine University of Pittsburgh Pittsburgh, Pennsylvania
References 1. Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR: TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 9:298-308, 2008 2. Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M: GFR alpha3 is expressed predominantly in nociceptive sensory neurons. Eur J Neurosci 13:2177-2182, 2001 3. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM: Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410-6415, 2004