Depression of intracranial self-stimulation in male and female rats by intraperitoneal lactic acid: effects of morphine, ketoprofen, and interactions with G-protein biased kappa opioid agonists.

Introduction: Numerous pharmacological classes of compounds have been explored as novel and efficacious alternatives to standard mu opioid agonist analgesics. We and others have described G-protein biased kappa opioid agonists as having potential utility as analgesics due to a lower propensity to produce sedation and dysphoria, which are thought to be mediated in large part through beta-arrestin signaling.

Methods: Here we compare two G-protein biased kappa agonists that differ in their basic chemical scaffold, triazole 1.1 (Tr1.1) and isoquinolinone 2.1 (Iso2.1), for alteration of intracranial self-stimulation (ICSS) in male and female rats. Lactic acid (LA) was given i.p. at a concentration sufficient to produce moderate to severe depression of ICSS.

Results: Neither Tr1.1 nor Iso2.2 reversed the effects of lactic acid at concentrations that produced significant depression of ICSS in either sex. Neither drug altered ICSS in the absence of lactic acid administration. In both males and females, morphine reversed the effects of i.p. lactic acid on ICSS and co-administration of Tr1.1 did not alter the dose-effect curve for morphine in either sex. Similar effects were observed for ketoprofen. Ketoprofen also reversed the effects of i.p. lactic acid on ICSS in both sexes in a dose-dependent manner, and co-administration of neither Tr1.1 nor Iso2.1 altered the ketoprofen dose-effect curve.

Conclusions: These data suggest that these G-protein biased kappa agonists may lack sufficient efficacy or potency to alter the effects of opioids or NSAIDs against moderate to severe antinociceptive stimuli in rats, and development of more potent or efficacious compounds may be required to demonstrate efficacy in rat models of moderate to severe nociception.