Effect of naltrexone on neuropathic pain in mice locally transfected with the mutant μ-opioid receptor gene in spinal cord.

Abstract

Opioid antagonists, such as naloxone and naltrexone, exhibit agonistic properties at the mutated μ receptor, MOR-S196ACSTA. In our previous study, systemic naloxone (10 mg·kg(-1) , s.c.) elicited antinociceptive effect without the induction of tolerance, dependence or rewarding effect in mice 2 weeks after intrathecal administration of double-stranded adeno-associated virus-MOR-S196ACSTA-eGFP. Here, we have investigated if this antinociceptive paradigm would be effective in a mouse model of neuropathic pain. Spinal nerves were ligated in male C57BL/6 mice 3 or 4 weeks after intrathecal injection of the lentivirus encoding the construct of MOR-S196ACSTA-eGFP (LV-MOR-S196ACSTA). Anti-allodynic effects of daily s.c.injections of saline, naltrexone (10 mg·kg(-1) ) or morphine (10 mg·kg(-1) ) were assessed by the von Frey test. After 14 days of treatment with saline, naltrexone or morphine, signs of natural withdrawal were measured at 22 and 46 h after the last injection. To determine the rewarding effects induced by morphine or naltrexone, the conditioned place preference test was carried out. Anti-allodynic effects, as measured by von Frey test, increased after naltrexone or morphine treatment in mice transfected with LV-MOR-S196ACSTA in the spinal cord. Cessation of treatment with morphine, but not naltrexone, induced natural withdrawal and rewarding effects. Systemic injection of naltrexone after the expression of a mutant μ opioid receptor, MOR-S196ACSTA, in the spinal cord may have therapeutic potential for chronic neuropathic pain, without the development of dependence or addiction. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.