Cellular signaling mechanisms that drive persistent hyperexcitability in nociceptors

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

Project Summary Chronic pain is notoriously insensitive to treatment with opioids. This research project aims to uncover signaling mechanisms in sensory neurons that are important for persistent pain and opioid resistance. In addition, the project aims to test new potential treatment options for ongoing pain using rat models of spinal cord injury (SCI) and surgical injury. Ongoing or spontaneous activity in primary nociceptors contributes to the maintenance of many forms of chronic and persistent pain, including pain after SCI or surgical injury. This project extends findings that i) chronic nociceptor hyperexcitability after SCI requires signaling through multiple cAMP effectors and crosstalk with the Ras/MAPK pathway, ii) SCI reduces AC inhibition by Gαi/o and thus the potency of opioids (DAMGO, morphine) on dorsal root ganglion (DRG) neurons, and iii) unexpectedly, gabapentinoid drugs (gabapentin and pregabalin) that often are used for treatment of neuropathic pain reverse both SCI-induced DRG neuron hyperexcitability and opioid resistance due to inhibition of L-type voltage-gated calcium channels (VGCC). This project explores the novel prediction that FDA-approved L-VGCC inhibitors can enhance opioid treatment of severe pain. Recent findings also suggest potential roles for L-VGCC inhibitors in treating surgical pain, which unlike SCI, can resolve but reappear after an injury heals. Preliminary findings indicate that nociceptor hyperexcitability, like pain sensitization, remains latent for long periods after remission of postsurgical pain because of continuing activation of opioid receptors. Three related hypotheses will be tested: 1) sustained membrane depolarization occurring after SCI decreases opioid sensitivity via opening of L-VGCC to activate C-Raf, with downstream ERK activation combined with cAMP signaling driving nociceptor hyperactivity and consequent chronic pain; 2) the same signaling loops promote opioid resistance in human DRG neurons, and 3) after surgical injury—representing conditions where pain resolves while a latent sensitization persists—these mutually reinforcing mechanisms are readily retriggered to reinstate nociceptor hyperactivity and enhanced pain. These hypotheses will be addressed with biochemical, high content imaging, whole-cell patch electrophysiology, and sophisticated behavioral methods in three specific aims. Aim 1) Determine contributions of L-type voltage-gated calcium channel signaling to human and rat opioid resistance, nociceptor hyperactivity, and rat pain behavior. Aim 2) Define molecular mechanisms that drive opioid resistance and hyperexcitability of nociceptors. Aim 3). Define signaling mechanisms regulating nociceptor hyperexcitability and associated pain after surgical injury. Importantly, our model identifies multiple drugs that have been FDA-approved for other applications but offer promise for both enhancing endogenous opioid responses and reducing the nociceptor hyperactivity that drives ongoing pain and central sensitization after many forms of severe injury.