Columbia University, New York, New York
Background: The use of opioid-based therapies in patients with chronic pain is a challenge in the medical practice because of drug abuse liability. This problem is magnified in the case of patients with a previous history of opioid abuse leading to reduced treatment of pain conditions in this population. Surprisingly, few studies have investigated how chronic pain could alter opioid intake patterns and none of them have focused in an opioid dependent population. In addition, although it is known that opioid reinforcement is mediated through the activation of the mesolimbic dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), there is uncertainty about the effects of pain on DA transmission within these brain areas and whether pain-induced effects on DA transmission within the VTA-NAc pathway may impact the reinforcing properties of opioids.
Methods: In the present study, we investigated the effects of chronic inflammatory pain on i.v. heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. We selected the complete Freund’s adjuvant (CFA) rat model of inflammation to assess the effect of chronic inflammatory pain on opioid abuse. In addition, we investigated the neurochemical changes induced by chronic inflammatory pain on DA transmission within the mesolimbic pathway by conducting in vivo microdialysis studies. All experimental protocols in animal studies were approved by the Institutional Animal Care and Use Committee at Columbia University.
Results: First, to examine whether the injection of CFA could affect the correct performance of the self-administration task we analyzed the effect of CFA-induced chronic inflammation on sucrose intake under a FR2 schedule, 2 and 7 days after saline or CFA injection. Neither CFA nor saline injection altered the number of correct responses vs the number of incorrect responses during sucrose FR2 self-administration sessions, indicating that CFA injection does not affect the correct performance of this task. Next, we studied motivated behavior for heroin self-administration. Seven days following iv cannulation, animals were placed in the operant chamber and trained to self administer sucrose until they could complete three consecutive sessions by self administering 60 sucrose pellets per session. Once the animals acquired the self administration behavior, they were given 2 h access to heroin (50 μg/kg/infusion) under FR1 schedule. After stable drug intake was obtained (defined as 5 consecutive sessions in which the number of infusions did not vary by more than 15% of the mean value obtained across those sessions), the number of responses required for an infusion was increased to 2 and then to 5 for a total of 6 sessions. Then, all animals underwent an initial PR session, where the number of correct responses increases exponentially with each administration, to measure their basal motivation for heroin (50 μg/kg/infusion). Two additional PR sessions at two different time points (2 and 7 days after CFA or saline injection, respectively) were conducted. Pain decreased the breakpoint (maximum number of responses that the animal completes in order to receive a reward) at the two time points tested after CFA injection for heroin at a dose of 50 μg/kg/infusion. These data indicate that CFA-induced pain impacts motivated behavior for self-administration at this lower dose of heroin. Next, we investigated whether this decrease in the break point induced by pain was dependent on the dose of heroin. Animals were trained under FR1 and FR2 schedules (50 μg/kg/infusion heroin) and 2 days after CFA or saline injection they were placed again in the operant box to generate a ‘within-session’ dose response curve. One of three doses of heroin (50, 100, 200 μg/kg/infusion) was made available for a 1-h time period during the session, with a 15-min resting period between doses. Doses were altered by varying the infusion duration. The presentation of the doses was made in an ascending or descending manner. Both dose-response curves showed a deviation from the expected linear dose-response for heroin, suggesting a possible change in the sensitivity (ie of the reinforcing properties) to heroin in the presence of chronic inflammatory pain. Finally, in order to determine whether these pain-induced altered patterns of opioid self-administration were related to the effects of chronic inflammatory pain on DA transmission within the VTA-NAc pathway we conducted in vivo microdialysis studies in CFA- and saline-injected rats. We found that chronic inflammatory pain blunted the effects of a 50 μg i.v. heroin challenge on DA release in the NAc.
Conclusions: These data suggest that chronic inflammatory pain may produce a rightward shift in the rewarding properties of heroin in opioid dependent rats, such that higher doses of heroin are needed for reliable rates of self-administration. In addition, our findings indicate that these effects may be related to an attenuation of DA transmission within the VTA-NAc pathway triggered by the presence of chronic inflammatory pain. Therefore, these data suggest that chronic inflammatory pain induces changes in the VTA-NAc pathway which in turn may facilitate opioid dose escalation in order to maintain the rewarding properties of the drug.
Keywords: pain, opioid abuse, self-administration, Nucleus accumbens, dopamine.
Disclosures: J. Moron-Concepcion, Nothing to Disclose; L. Hipolito-Cubedo, Nothing to Disclose.