Neuropathic pain symptoms respond poorly to currently available therapeutics, with most patients reporting unrelieved pain and significant impairment in quality of life as a result. A prerequisite for design of better therapeutics is a moe thorough understanding of this pathological condition. Recently, several convincing studies have demonstrated a role for purinergic signaling in the development of neuropathic pain. These studies have identified events downstream of the purinergic receptors that promote neuropathic pain, from functional changes within particular cell types to effects on the larger neural circuitres that modulate pain sensations. However, a major missing component from this prevailing model that is centered on paracrine purinergic signaling is information regarding the source and mechanism of release for the nucleotides that serve as purinergic agonists (e.g., ATP). In this proposal, I ask whether the ATP-permeable pannexin 1 (Panx1) channel contributes to neuropathic pain. My preliminary data suggests that, indeed, Panx1 does contribute to neuropathic pain. I found that Panx1 global knockout mice are protected from hypersensitivity following in two sciatic nerve injury models (chronic constriction and spared nerve injury). Moreover, this result was replicated in mice given Panx1 blockers at the time of injury, suggesting that Panx1 may be important early after peripheral nerve injury. Here, I propose to confirm these preliminary findings and also identify when (early or late) and where (central vs. peripheral;neurons, glia or inflammatory cells) Panx1 is necessary during the development/maintenance of neuropathic pain, using novel conditional mouse models and pharmacological tools. These studies advance understanding of the mechanisms that contribute to neuropathic pain, and suggest Panx1 as a novel target that may be exploited to intervene therapeutically in the process.
Neuropathic pain constitutes a significant individual and societal burden and is notoriously difficult to treat. Novel therapeutics can be rationally designe to target mechanisms that promote neuropathic pain, such as those related to purinergic signaling. This proposal investigates whether pannexin 1, a plasma membrane channel known to release ATP and promote purinergic signaling, contributes to neuropathic pain.
|Weaver, Janelle L; Arandjelovic, Sanja; Brown, Gregory et al. (2017) Hematopoietic pannexin 1 function is critical for neuropathic pain. Sci Rep 7:42550|