Therapeutic potential and the critical site of action of non-addicting glibenclamide in neuropathic pain

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BACKGROUND: Almost half of Veterans experience chronic pain, which is disproportionately greater than the 25 million Americans in the civilian population who suffer from significant chronic pain. Chronic pain is a common sequela of military- and terror-related injuries. The majority of battlefield wounds involve injuries to exposed limbs, resulting in high rates of neuropathic pain caused by damage to a peripheral nerve. Opioid use disorder and the ongoing “opioid epidemic” are driven in part by the legitimate use of opioids prescribed for neuropathic pain. Post-deployment, 15% of military Veterans use opioids, compared to 4% of the general population, and in Veterans, there is a direct correlation between the use of opioids and suicide. Targeting alternative non-opioid pathways for pain control using non-addicting drugs is a major goal of neuropathic pain research. After peripheral nerve injury (PNI), cytokines and chemokines are upregulated centrally, including in dorsal horn astrocytes, where they contribute mechanistically to the pathogenesis of neuropathic pain. Reactive astrocytes in the dorsal horn exhibit a chronically activated, pro-inflammatory secretory (CAPS) phenotype characterized by the secretion of numerous factors, including interleukin-6 (IL-6), chemokine C-C motif ligand 2 (CCL2) and chemokine C-X-C motif ligand 1 (CXCL1), each of which individually has been shown to contribute to neuropathic pain behaviors. The post-PNI astrocytic CAPS phenotype contributes to both inflammation and neuronal hyperactivation via neuronal chemokine receptors, leading to neuropathic pain. Our pilot data demonstrate the novel findings that, in the murine sciatic nerve cuff model of neuropathic pain, inhibiting sulfonylurea receptor 1 (SUR1) with low-dose glibenclamide administered daily over several weeks, with treatment beginning during the chronic phase at day21 after PNI, causes marked reductions in: (i) mechanical allodynia, thermal hyperalgesia and place escape/avoidance; (ii) dorsal horn astrocyte expression of IL-6, CCL2 and CXCL1. DESCRIPTION: This project has the clinically relevant aim of establishing the therapeutic potential, durability, and critical site of action of glibenclamide treatment in neuropathic pain behaviors induced by PNI. Four separate experiments are planned in males and females using the murine sciatic nerve cuff model, with treatments applied only during the chronic phase, 3 weeks after PNI. In these experiments, we will examine: (a) the ability of various doses of systemic and intrathecal glibenclamide to effectively reverse neuropathic pain behaviors (mechanical allodynia, thermal hyperalgesia, place escape/avoidance, anxiety and depression-like behaviors), and related motor dysfunction; (b) the ability of systemic glibenclamide to gradually extinguish neuroinflammation in the DRG/dorsal horn, for correlation with the observed gradual extinction of allodynia; (c) the durability of glibenclamide treatment after treatment cessation; and (d) the anatomical and cellular site of action of glibenclamide. Mice will be studied up to 11 weeks for neuropathic pain behaviors and motor function; DRG and dorsal horn tissues will be studied for neuroinflammation, including astrocyte and microglial activation, and expression of SUR1-TRPM4, IL-6, CCL2 and CXCL1. This project is the first to study the effects in neuropathic pain of SUR1 inhibition by glibenclamide, which is safe, non-addicting and could be repurposed for the treatment of neuropathic pain, thereby greatly improving the function of affected Veterans.