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Papers of the Week

Papers: 27 Jan 2024 - 2 Feb 2024

2024 Jan 26

J Pharmacol Exp Ther


12-(S)-Hydroxyeicosatetraenoic acid and GPR31 signaling in spinal cord in neuropathic pain.


Giancotti LA, Lauro F, Olayide I, Zhang J, Arnatt CK, Salvemini D


Neuropathic pain is a pressing unmet medical need requiring novel non-opioid based therapeutic approaches. Using unbiased transcriptomic analysis, we found that the expression of , a G protein-coupled receptor, increased in the dorsal horn of the spinal cord in rats with traumatic nerve injury-induced neuropathic pain. Daily intrathecal injections of si reversed behavioral hypersensitivities in a time-dependent manner. GPR31, a G protein-coupled receptor, has recently been cloned and is a receptor for 12-(S)-hydroxyeicosatetraenoic acid (12-(S)-HETE). The lack of commercially available GPR31 antagonists has hampered the understanding of this receptor in pathophysiological states, including pain. To investigate this, our first approach was to identify novel GPR31 antagonists. Using a multidisciplinary approach, including an approach, we identified the first highly potent and selective small molecule GPR31 antagonist, SAH2. Here, we characterize the pharmacological activity in well-described models of neuropathic pain in rodents and provide evidence that 12-(S)-HETE/GPR31-dependent induced behavioral hypersensitivities are mediated through MAPKs activation in the spinal cord. Our studies provide the pharmacological rationale for investigating contributions of GPR31 along the pain neuroaxis and the development of non-opioid GPR31-targeted strategies. We have identified the first highly selective GPR31 antagonist. Using this antagonist, we have demonstrated that GPR31 signaling in the spinal cord is pronociceptive and provided signaling mechanisms downstream of GPR31 activation implicated in these processes.