Analgesic Effects Of Asp3662, A Novel 11 Beta-Hydroxysteroid Dehydrogenase 1 Inhibitor, In Rat Models Of Neuropathic And Dysfunctional Pain

BACKGROUND AND PURPOSEGlucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11 beta-HSD1 inhibitor, on neuropathic and dysfunctional pain.EXPERIMENTAL APPROACHThe enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats.KEY RESULTSASP3662 inhibited human, mouse and rat 11 beta-HSD1 but not human 11 beta-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats.CONCLUSIONS AND IMPLICATIONSASP3662 is a potent, selective and CNS-penetrable inhibitor of 11 beta-HSD1. The effects of ASP3662 suggest that selective inhibition of 11 beta-HSD1may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.