Nociceptive hypersensitivity often accompanies tissue damage. This hypersensitivity is a crucial defense mechanism that fosters protective behaviors, typically “nocifensive” aversive withdrawal responses, while the damaged tissue heals. Two common forms of hypersensitivity are allodynia, in which normally nonnoxious stimuli elicit a nociceptive response, and hyperalgesia, an exaggerated responsiveness to noxious stimuli. Normally, nociceptive hypersensitivity only persists until tissue repair is complete. Unfortunately, in certain cases, both allodynia and hyperalgesia can persist long after healing is complete, resulting in chronic pain. This disease is highly prevalent and difficult to treat, leading to widespread disability and suffering and a tremendous cost to society. Currently available analgesic drugs have serious limitations. In the case of opiates, which for many centuries have been a primary treatment for chronic pain, serious side effects such as tolerance (decreased analgesic effect over time), physical dependence, nausea, respiratory depression, and the perceived risk of addiction have limited the effectiveness of these drugs in chronic pain treatment. These limitations have prompted a broad search for new analgesic targets [1
Mammalian studies have identified a plethora of molecular mediators of nociceptive sensitization. These include lipids, cytokines, neuropeptides, and ions that are secreted from cells within damaged tissue or from circulating blood cells recruited to the site of damage [2
]. Ultimately, these factors are thought to modulate the activity of the ion channels present on nociceptive sensory neurons that normally gate in response to noxious thermal, mechanical, or chemical stimuli. One notable class of such receptors is the transient receptor potential (TRP) channel family. For example, transient receptor potential vanilloid-1 (TRPV1) plays an important role in both nociception and inflammatory hyperalgesia in mice [3
Might there be additional mediators that cause nociceptive sensitization? In addition to the factors noted above, secreted developmental morphogens such as Hedgehog (Hh) can be released from dying cells and can mediate compensatory proliferative responses following tissue damage [5
]. Hh regulates diverse developmental processes in a variety of tissues including embryonic patterning [10
], cell fate specification [11
], axon guidance [12
], and proliferation [14
]. However, other than involvement in cellular proliferation [15
] and cancer [16
], the roles of Hh in the physiology of differentiated tissues are not clear. In particular, it is currently unknown whether morphogens such as Hh, when released from damaged cells, can also alter the physiological sensitivity of nociceptive sensory neurons.
has recently become a useful tool for identifying conserved genes required for nociception and nociceptive sensitization. For example, Drosophila
larvae exhibit a unique nocifensive withdrawal response when challenged with a noxious thermal or mechanical stimulus. Such stimuli are detected by class IV dendritic arborization neurons, which are required for the behavioral response [17
]. Various assays of nociception in flies have identified Painless, a TRP channel that is required for thermal and mechanical nociception [18
transient receptor potential channel A1 (dTRPA1), a TRP channel required for responses to noxious chemical stimuli [19
]; Pickpocket, a degenerin epithelial sodium channel (DEG/ENaC) protein required for responsiveness to noxious mechanical stimuli [20
]; and the straightjacket channel required for thermal nociception in adult flies [21
]. We recently introduced a Drosophila
model of ultraviolet irradiation (UV)-damage-induced nociceptive sensitization [22
] in which the Drosophila
tumor necrosis factor (TNF) ortholog and its receptor are required for sensitization, as in vertebrates [23
]. This work demonstrated that the signaling mechanisms that modulate nociceptive sensitivity are also well conserved. In an effort to identify novel regulators of nociceptive signaling, we sought to test whether other classes of molecules released from damaged or dying cells play a role in the development of nociceptive hypersensitivity.
Here we establish that Hh can mediate two types of nociceptive sensitization, thermal allodynia and hyperalgesia. In Drosophila larvae, these actions occur in parallel to TNF signaling and appear to act via distinct TRP channels in nociceptive sensory neurons. Whereas Painless is required for the development of Hh- or TNF-induced thermal allodynia, dTRPA1 is required for Hh-induced thermal hyperalgesia. We also find that a pharmacological blockade of Sonic Hedgehog (Shh) signaling in rats interacts with opioid receptor signaling in standard models of both inflammatory and neuropathic pain. Our findings reveal a novel physiological role for Hedgehog signaling, and thus identify new potential therapeutic targets for the treatment of chronic pain.