The use of buprenorphine/naltrexone combination treatment in attenuating relapse to morphine/methamphetamine polydrug-dependence in mice

Abstract

Currently, there is an increasing pattern of methamphetamine abuse among opioid users and yet there is no pharmacological treatment approved by Food and Drug Administration (FDA) to treat methamphetamine dependence. Since kappa-opioid receptor has been associated with relapse to many drugs of abuse, this receptor might have the potential to prevent relapse to both methamphetamine and opioid. Therefore, this study aims to investigate the involvement of the kappa-opioid receptor system in relapse related to morphine/methamphetamine (polydrug) addiction. Firstly, naltrexone was assessed in a tail-withdrawal test to ensure its ability in suppressing the mu-opioid receptor activity of buprenorphine in mice at 52 °C warm water bath. The tail-withdrawal test was also used to identify the minimum dose of methamphetamine that can produce analgesic effects in order to determine the dose responsible in activating the mu-opioid receptor. Both of these assays were crucial since this study aims to investigate the involvement of kappa-opioid receptor rather than the rest of opioid receptor (e.g. mu-opioid receptor) in preventing drug relapse. Next, conditioned place preference (CPP) test was used to investigate the ability of the treatment candidates (buprenorphine/naltrexone combination and norbinaltorphimine, nor-BNI) in drug relapse model in mice. Method validation and optimisation for the CPP test were conducted prior to the test to ensure that the conditioning and priming dose, confinement time as well as time interval applied in the test are optimum. Then, the CPP test was conducted to compare the ability of these two treatment regimes in attenuating reinstatement to morphine-, methamphetamine- and morphine/methamphetamine polydrug-dependence. Based on the result, 1.0 mg/kg naltrexone pretreatment successfully block the mu-opioid receptor agonist activity of 0.3 mg/kg buprenorphine by showing a decrease in tail-withdrawal latency in the tail-withdrawal test. This proved that the combination of buprenorphine/naltrexone treatment is able to mask the mu-opioid receptor agonism of buprenorphine and act as a functional kappa-opioid antagonist. Moreover, it was found that the minimum dose of methamphetamine that can produce analgesic effect in the tail-withdrawal test is at 5.0 mg/kg. Hence, 1.0 mg/kg methamphetamine used in the CPP test will have no effect on the mu-opioid receptor and any dependence induced at this dose is not related to the mu-opioid receptors activity. In the CPP test, the combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone pretreatment (ip) was able to attenuate morphine- (7.5 mg/kg, ip) and morphine/methamphetamine (7.5 mg/kg and 1.0 mg/kg, ip respectively) polydrug-reinstatement but not methamphetamine-reinstatement (1.0 mg/kg, ip). However, pretreatment with 10.0 mg/kg norbinaltorphimine (a selective kappa-opioid antagonist) only attenuated morphine-reinstatement but not methamphetamine- and morphine/methamphetamine polydrug-reinstatement. Therefore, it can be suggested that methamphetamine and morphine/methamphetamine polydrug-dependence may involve other important receptors and neurocircuit besides the kappa-opioid receptor. Further studies on immunohistochemistry and autoradiography may be crucial to rule out the involvement of kappa-opioid receptor in mediating relapse to morphine-, methamphetamine- or morphine/methamphetamine polydrug-dependence.