Differential Effects of Opioid Versus Alcohol Dependence on Pain Avoidance Behavior and Regional Endocannabinoid System Deficiency

In contrast to their analgesic effects, chronic use of opioids or alcohol often creates the paradoxical emergence of heightened pain sensitivity, termed hyperalgesia, during withdrawal. A hallmark symptom of hyperalgesia is the development of motivational strategies to avoid painful stimuli, and we have shown that adult male Wistar rats display pain avoidance behavior using the mechanical conflict avoidance system when in withdrawal from morphine (n=10–11/group) and alcohol (n=8–9/group). The present study seeks to identify how morphine and alcohol differentially affect pain avoidance behavior and endocannabinoid signaling within pain‐ and avoidance‐ associated brain regions, including the periaqueductal grey (PAG) and basolateral amygdala (BLA).Morphine dependence was induced via daily subcutaneous morphine injections (escalating dose of 10–20mg/kg) over 3 weeks. Alcohol dependence was induced via exposure to chronic intermittent ethanol vapor (CIEV) for 14 hours per day for 8 weeks. Pain avoidance behavior was quantified using the MCS as the latency for rats to exit a brightly lit start chamber onto nociceptive probes of varying heights (0–5mm) to enter a dark goal box. Western blotting was conducted for quantification of endocannabinoid system‐related proteins cannabinoid receptor 1 (CB1R) and eCB synthetic and catabolic enzymes diacylglycerol lipase alpha (DAGLa), monoacylglycerol lipase (MAGL).We found that morphine and alcohol dependence produced distinct patterns of pain avoidance behavior, where morphine dependence produced a hyperalgesic behavior and ethanol dependence produced an allodynic phenotype. This behavior negatively correlated with PAG levels of CB1R and DAGLa in morphine dependent animals and with the ratio of BLA DAGLa:MAGL in alcohol dependent animals, reflective of a decreased eCB tone in these animals. This suggests that exogenous cannabinoid treatment may be an effective therapy for substance‐induced hyperalgesia. Because substance‐induced hyperalgesia and negative affective components of pain are integral to addiction reinforcement, targeting these behaviors therapeutically could treat substance abuse.Support or Funding InformationNIAAA: T32AA007577, R00AA020839, R01AA025996, R21AA025736, NIH‐NICHD‐2018‐05