Multidimensional quantification of pain responses using novel rat pain scale reveals the absence of opioid induced hyperalgesia following chronic contingent and non-contingent morphine exposure in rats.

Abstract

Opioids are often prescribed to treat chronic and post-operative pain, but there is data to suggest that opioid exposure can lead to hyperalgesia or allodynia, referring to increases in pain sensitivity to painful and innocuous stimuli, respectively. This paradoxical phenomenon has been observed in the clinic as early as the 1800s and has been modeled numerous times in pre-clinical models of opioid exposure. Opioid induced hyperalgesia (OIH), however, has been met with criticism from clinicians and pre-clinical models do not always mirror clinical opioid use. Here, we explore reflexive responses to mechanical stimuli following chronic contingent and non-contingent morphine exposure after 1 day and 1 week of abstinence. The pain responses were quantified using a high-speed videography-based rodent pain scale, machine learning, and mathematical models. This model combines paw kinematics (speed, height, etc.) with nocifensive behaviors (eye grimace, paw shake, etc.) into a single composite pain score. Males did not exhibit OIH following morphine self-administration, and males and females did not exhibit OIH following experimenter-delivered morphine injections. Hargreaves hot plate assay results complement this data, showing no indication of opioid induced hyperalgesia. Numerous pre-clinical models use drug exposure regimens that are incongruent with doses and patterns prescribed to chronic pain and post-operative patients. Thus, the regimen presented in this study strives to mirror patient drug-taking patterns, providing a key model for the exploration of opioid induced hyperalgesia. Thus, our results complement the current clinical literature, where opioid induced hyperalgesia is not always observed consistently in the patient population.