Investigating the Role of Dopamine in Opioid Reward in Chronic Neuropathic Pain

Abstract

Background: Neuropathic (NP) pain is commonly treated with opioids, such as morphine, despite acknowledgement that these drugs produce long-term complications including tolerance and addiction. Opioids have two effects on NP pain: they reduce negative sensations (i.e., pain relief) and produce positive affect (i.e., reward). The latter, mediated through the mesolimbic dopamine (DA) pathway, is linked to the addictive potential of commonly misused drugs. The goal of this project was to examine DA mechanisms in the positive and negative reinforcing effects of opioids in chronic NP pain. Methods: NP pain was induced in male Long-Evans rats using chronic constriction injury (CCI) of the sciatic nerve. A one-sided conditioned place preference (CPP) paradigm provided independent measures of positive and negative reinforcement. NP and sham-lesioned rats (6-13 days post-surgery) underwent four CPP conditioning sessions, every other day, in which they were confined to either a morphine- or saline-paired compartment for 30 min. On intervening days, they received the alternate injection and were left in the home cage. On test day, drug-free rats had free access to all compartments for 30 min: increased time spent in the drug-paired compartment reflects a CPP whereas decreased time spent in the saline-paired compartment reflects a conditioned place aversion (CPA). The role of DA mechanisms in CPP and CPA was assessed in separate groups of rats that received injections of the non-specific DA antagonist, flupenthixol, prior to morphine injections. Results: NP rats showed a CPA to the vehicle-paired (i.e., pain-paired) side, whereas sham-lesioned rats did not. A low dose of morphine reduced the CPA (negative reinforcement), which was not blocked by DA antagonism. A higher dose of morphine produced a CPP (positive reinforcement), which was blocked by DA antagonism at a lower dose in sham-lesioned compared to NP rats. Conclusions: The positive and negative reinforcing effects of opioids may be differentially mediated in chronic NP pain. In addition, opioids may be more rewarding in chronic NP pain states, possibly due to the combination of positive and negative reinforcement.