Pharmacology/Drug Development

Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms underlying CRPS are unknown, the syndrome is associated with central and autonomic nervous system dysregulation and peripheral hyperalgesia symptoms. These symptoms also manifest in alcoholic neuropathy, suggesting that the two conditions may be pathophysiologically accretive. Interestingly, people assigned female at birth (AFAB) appear to be more sensitive to both CRPS and alcoholic neuropathy. To better understand the biobehavioral mechanisms underlying these conditions, we investigated a model of combined CRPS and alcoholic neuropathy in female rats. Animals were pair-fed either a Lieber-DeCarli alcohol liquid diet or a control diet for ten weeks. CRPS was modeled via unilateral hind limb cast immobilization for seven days, allowing for the other limb to serve as a within-subject control for hyperalgesia measures. To investigate the role of circulating ovarian hormones on pain-related behaviors, half of the animals underwent ovariectomy (OVX). Using the von Frey procedure to record mechanical paw withdrawal thresholds, we found that cast immobilization and chronic alcohol drinking separately and additively produced mechanical hyperalgesia observed 3 days after cast removal. We then examined neuroadaptations in AMPA GluR1 and NMDA NR1 glutamate channel subunits, extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) in bilateral motor and cingulate cortex across all groups. Consistent with increased pain-related behavior, chronic alcohol drinking increased GluR1, NR1, ERK, and CREB phosphorylation in the cingulate cortex. OVX did not alter any of the observed effects. Our results suggest accretive relationships between CRPS and alcoholic neuropathy symptoms and point to novel therapeutic targets for these conditions.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of , a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

Chronic constriction injury (CCI) of the sciatic nerve was used to establish neuropathic pain (NP) models in rats. CCI rats were then treated with propofol and their paw withdrawal mechanical threshold (PWMT) and paw withdraw thermal latency (PWTL) were measured. In addition, the expression patterns of TNF-α, IL-1β and IL-10 were detected. CCI rats treated with propofol were further injected with antagomiR-140-3p to verify the role of miR-140-3p in propofol's analgesic actions. In addition to confirming the relationship between miR-140-3p and JAG1, the expression patterns of JAG1 itself were detected. Propofol-treated CCI rats were also injected with Ad-JAG1 to test the role of JAG1 in propofol's analgesic mechanism of action. Finally, the levels of JAG1 and Notch pathway-related proteins were detected.Results: Propofol was found to alleviate NP, including thermal hyperalgesia and mechanical pain threshold. Propofol could also ameliorate neuroinflammation by up-regulating the expression of IL-10 and inhibiting the release of TNF-α and IL-1β. Mechanically, propofol enhanced the amount of miR-140-3p in CCI rats via regulation of JAG1. Down-regulation of miR-140-3p, or up-regulation of JAG1, could reduce the protective effect of propofol against NP. Propofol inhibited the activation of Notch signaling via miR-140-3p/JAG1 to realize its analgesic effect. Conclusion: Our findings indicated that propofol inhibits inflammatory responses and the Notch signaling pathway via miR-140-3p/JAG1 to alleviate NP. These data provide evidence to support a potential clinical therapy for NP. This article is protected by copyright. All rights reserved.