Neurobiological Correlates of Pain Avoidance Behavior in Opioid vs. Alcohol Dependence

Abstract

In contrast to their analgesic properties, excessive use of either alcohol or opioids produces a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may promote further drinking or use of opioids to manage worsening pain symptoms. Hyperalgesia has traditionally been measured in rodents via reflex‐based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of alcohol/opioid dependence and withdrawal, we employed a recently developed non‐reflex‐based method for measuring pain avoidance‐like behavior in animals (Mechanical Conflict Avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid‐dependent group) or repeated saline (control group). Morphine‐dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. Such pain avoidance‐like behavior exhibited a modest correlation with mechanical paw withdrawal thresholds as measured via the von Frey method (r=−0.4413, p=0.0452), indicating that the two behavioral assays measure overlapping but not entirely similar pain‐like conditions. We next investigated individual relationships between pain avoidance‐like behavior and alterations in protein phosphorylation in central motivation‐related brain areas. We discovered that pain avoidance‐like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate‐limiting enzyme for dopamine synthesis (TH) across specific brain regions. Separate groups of male Wistar rats were made dependent on alcohol via exposure to chronic, intermittent ethanol vapor and compared to air‐exposed (non‐dependent) controls. Here, alcohol‐dependent animals exhibited enhanced pain avoidance‐like behavior of shorter probe heights that were innocuous (i.e., not avoided) in non‐dependent animals, indicative of a state of allodynia. We are currently examining the neural correlates of pain avoidance in these groups to compare to our results in opioid‐dependent animals. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain, and that qualitatively distinct dimensions of pain avoidance‐like behavior (hyperalgesia vs. allodynia) may exist in opioid‐ vs. alcohol‐dependent animals.Support or Funding InformationNational Institute on Alcohol Abuse and Alcoholism (T32AA007577, ARP; R00AA020839, SE), LSUHSC School of Medicine start‐up funds.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.