In vivo characterization of 6ß‐naltrexamine, a putative opioid neutral antagonist

Abstract

Opioid analgesics remain a mainstay for the treatment of acute and chronic pain. The use of these agents is associated with significant side effects including addiction and gastrointestinal (GI) dysfunction. Our laboratory has previously reported on the in vivo pharmacology of 6ß‐naltrexol, an active metabolite of naltrexone and a putative neutral antagonist. The current studies assessed the in vivo pharmacology of a related compound, 6ß‐naltrexamine, which also acts as a neutral antagonist in opioid‐exposed cell systems. I.v. administration of 6ß‐naltrexamine, in male ICR mice, resulted in a time related blockade of the antinociceptive effects of i.v. hydrocodone, ID50 value (95% CI) of 2.03 (1.68–2.46) mg/kg. The antagonist had a peak effect at 60 minutes and duration of action of approximately 90 minutes in the 55°C tail‐flick test. 6ß‐naltrexamine also dose‐dependently reversed hydrocodone‐induced GI inhibition with an ID50 value (95% CI) of 4.14 (2.23–7.71) mg/kg. These results indicated that 6ß‐naltrexamine is a relatively potent opioid antagonist that exhibits a CNS/PNS potency ratio similar to naltrexone and naloxone. We are currently assessing the efficacy of 6ß‐naltrexamine in animal models of acute and chronic dependence.