Papers of the Week

Substance use disorders (SUDs) and overdose deaths have reached unprecedented levels despite considerable efforts to develop pharmacotherapies for their treatment and prevention. Chemoattractant cytokines ('chemokines') are immune system messengers that can alter the therapeutic and abuse-related effects of opioids and stimulants. Therefore, the aims of this study were to evaluate the effectiveness of Maraviroc, a CCR5 antagonist, and AMD3100, a CXCR4 antagonist, to alter 1) the self-administration of fentanyl, an opioid, and cocaine, a stimulant, using a food versus drug choice procedure and 2) the analgesic effects of fentanyl in a radiant heat assay. Adult male Sprague Dawley rats were trained to respond under a fixed ratio (FR) 5 on one lever to receive an infusion of fentanyl (n=8), and on an alternate lever to receive food (grain-based pellet). The choice procedure consisted of 5 sequential 20-min components, each separated by a 2-min intercomponent interval. Food was available across all five components, with increasing unit doses of fentanyl (0.00032-0.01 mg/kg/infusion) available during components 2-5; no drug was available during component 1. Once responding stabilized, rats underwent a series of drug pretreatment tests, including: naloxone (1, 3.2 mg/kg; IP), haloperidol (0.01-0.1 mg/kg; IP), Maraviroc (1-17.8 mg/kg; IP), and AMD3100 (1-17.8 mg/kg; IP). A separate cohort of 8 adult male Sprague Dawley rats was used to evaluate the effects of Maraviroc (10 mg/kg; IP), and AMD3100 (10 mg/kg; IP), on paw withdrawal latencies in a thermal nociception procedure following cumulative doses of fentanyl (0.01-0.1 mg/kg; IP). In rats responding for food or fentanyl, naloxone reduced fentanyl choice while increasing choice of food, whereas haloperidol had little effect on the choice for fentanyl, but decreased responding on both levers at large doses. Maraviroc and AMD3100 had similar effects all rats tested, effectively reallocating behavior away from the drug and towards the food reinforcer. At the largest dose tested, Maraviroc (17.8 mg/kg; IP) disrupted behavior in the early portions of the session, suggestive of a sedative effect in some animals. Maraviroc and AMD3100 did not significantly modify the analgesic effects of fentanyl during tests of thermal nociception. These data suggest that antagonism of CXCR4 and CCR5 may be of use in the ongoing effort to develop medications for the treatment of SUDs.