Hedgehog Signaling Regulates Nociceptive Sensitization

Abstract

Summary Background Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets. Results Here we use a Drosophila model of thermal nociceptive sensitization to show that Hedgehog (Hh) signaling is required for both thermal allodynia and hyperalgesia following ultraviolet irradiation (UV)-induced tissue damage. Sensitization does not appear to result from developmental changes in the differentiation or arborization of nociceptive sensory neurons. Genetic analysis shows that Hh signaling acts in parallel to tumor necrosis factor (TNF) signaling to mediate allodynia and that distinct transient receptor potential (TRP) channels mediate allodynia and hyperalgesia downstream of these pathways. We also demonstrate a role for Hh in analgesic signaling in mammals. Intrathecal or peripheral administration of cyclopamine (CP), a specific inhibitor of Sonic Hedgehog signaling, blocked the development of analgesic tolerance to morphine (MS) or morphine antinociception in standard assays of inflammatory pain in rats and synergistically augmented and sustained morphine analgesia in assays of neuropathic pain. Conclusions We demonstrate a novel physiological role for Hh signaling, which has not previously been implicated in nociception. Our results also identify new potential therapeutic targets for pain treatment.

The Anoctamin Family Channel Subdued Mediates Thermal Nociception in Drosophila

“…The thermo-TRP ion channels Painless and dTRPA1 are required for thermal nociception by class IV md neurons (5,10,11). Similarly, we show that the Subdued channel is activated by noxious temperatures and is required in sensory nociceptors for heat-induced nociceptive behaviors.…”

Endocannabinoids are conserved inhibitors of the Hedgehog pathway

“…Some of these may reflect their activity toward the Hh pathway. Cannabinoids and Hh signaling regulate many of the same processes-e.g., angiogenesis (6,38), hair follicle development (39,40), nocioception (5,41), bone formation (42,43), and energy metabolism (3,4,44). Indeed, cannabinoids block growth of tumors known to depend on Hh signaling (45)(46)(47)(48)(49)(50).…”

“…It is inappropriately activated in many tumors (2) and also influences physiological functions including lipid and sugar metabolism (3,4), nocioception (5), the response to ischemia (6), and immune activation (7,8). Different classes of compounds with activity toward Hh signaling could have broad therapeutic applications.…”

Temperature sensation in Drosophila

“…The md nociceptors have been used as a potential model for investigating these processes. Fly larvae exhibit both types of sensitization to heat after UV-elicited tissue damage 46 , and two evolutionarily conserved signaling pathways, the Tumour Necrosis Factor (TNF) 46 and Hedgehog (Hh) 47 pathways, are known to be involved in this sensitization. TNF signaling, also involved in mammalian nociceptor sensitization 48 , was specifically implicated in larval allodynia.…”