Activation of Peripheral μ-opioid Receptors by Dermorphin [d-Arg2, Lys4] (1–4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain

<jats:title>AbstractAbstract</jats:title> <jats:p>By using a model of male and female rats with spinal nerve ligation–induced neuropathic pain, the authors demonstrated that systemic administration of dermorphin [<jats:sc>d</jats:sc>-Arg2, Lys4] (1-4) amide, a highly selective μ-receptor agonist, attenuated both neuropathic mechanical and heat hypersensitivity through activation of μ-receptor at peripheral but not central sites. Further, the efficacy of dermorphin [<jats:sc>d</jats:sc>-Arg2, Lys4] (1-4) amide to inhibit heat hypersensitivity is greater than that to inhibit mechanical hypersensitivity.</jats:p> <jats:sec> <jats:title>Background</jats:title> <jats:p>Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [<jats:sc>d</jats:sc>-Arg2, Lys4] (1–4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation–induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA’s possible mechanisms of action in male rats.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber–mediated, but not A-fiber–mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine–induced [Ca<jats:sup>2+</jats:sup>] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.</jats:p> </jats:sec>