Hedgehog Travels a Painful Pathway

Sci. Signal.  04 Oct 2011:
Vol. 4, Issue 193, pp. ec272
DOI: 10.1126/scisignal.4193ec272

Tissue damage is frequently associated with exaggerated responses to potentially damaging stimuli; for instance, normally nonnoxious stimuli may elicit pain, and thereby aversive withdrawal (allodynia), or sensitivity to pain may be heightened, so that a noxious stimulus elicits an exaggerated response (hyperalgesia). Such nociceptive sensitization can persist after the initiating damage has healed, leading to chronic pain. Noting that morphogens such as Hedgehog (Hh) can be released from damaged tissues, Babcock et al. explored Hh’s role in mediating allodynia and hyperalgesia in a Drosophila model of nociceptive sensitization after ultraviolet (UV) irradiation. Twenty-four hours after UV exposure, the normally nonnoxious stimulus of 38oC elicited a withdrawal response in both control larvae and larvae bearing a temperature-sensitive Hh allele (hhts2) when larvae were maintained at a permissive temperature (18oC). When larvae were maintained at a restrictive temperature (29oC), however, only the control larvae exhibited this thermal allodynia. Similar analyses implicated Hh in hyperalgesia to a noxious stimulus of 45oC. Overexpression of Patched (which Hh binds to and inhibits) in nociceptive neurons inhibited allodynia and hyperalgesia, as did tissue-specific inhibition of Hh signaling through RNA interference or expression of dominant-negative forms of Hh effectors. In contrast, constitutive activation of Hh signaling led to exaggerated nociceptive responses in the absence of tissue damage. The Drosophila ortholog of tumor necrosis factor (TNF) had previously been implicated in UV-induced thermal allodynia, and experiments in which one pathway was activated while the other was inhibited indicated that TNF and Hh acted in parallel to mediate Drosophila thermal allodynia. Knockdown analyses implicated two TRP (transient receptor potential)–family ion channels in UV-induced thermal nociception, Painless and dTRPA1, with analyses of the responses after genetic activation of Hh or TNF signaling leading to a model in which Painless mediates TNF- or Hh-induced thermal allodynia, whereas dTRPA1 mediates Hh-induced thermal hyperalgesia. Pharmacological analysis of the role of Hh in a rat model revealed that, although the Smoothened inhibitor cyclopamine had no independent analgesic effect, it blocked analgesic tolerance to morphine in inflammatory pain and enhanced the analgesic response to morphine in neuropathic pain. Thus, the authors conclude that Hh signaling plays an unexpected role in modulating nociception and that components of the Hh pathway could provide targets for pain therapy.

D. T. Babcock, S. Shi, J. Jo, M. Shaw, H. B. Gutstein, M. J. Galko, Hedgehog signaling regulates nociceptive sensitization. Curr. Biol. 21, 1525–1533 (2011). [PubMed]