Effect of Chronic Inflammatory Pain on Rewarding Effects of Morphine in Male versus Female Rats
Authors: Gogulski Hannah Y. , Davis Seth M. , Craft Rebecca M. 
Published: June 2021

Morphine and other opioid analgesics are widely used to treat both acute and chronic pain conditions. While they are effective pain‐relievers, their action at the μ‐opioid receptor means that they are also rewarding, and their use can lead to addiction. Previous research indicates that pain may reduce the rewarding effects of morphine. In this study, we sought to compare morphine potency and efficacy to produce a conditioned place preference (CPP, a measure of reward) between rats that were in chronic pain and rats that were not. Because sex differences in morphine's rewarding and antinociceptive effects have been demonstrated, both male and female rats were conditioned using a three‐day conditioning paradigm. On day one, rats could freely explore both sides of the two‐sided conditioning apparatus. The sides differed in color (black versus white walls) and floor type (bars versus wire grid); the sides were divided by a small section of smooth metal on which the animal was initially placed. Time spent on each side of the apparatus and number of crosses between sides in 15 min were recorded. Then mineral oil vehicle or Complete Freund's Adjuvant (CFA) was injected into one hind paw. On day two, rats underwent two conditioning trials 6 h apart wherein morphine treatment was paired with one side of the apparatus and saline was paired with the other. Morphine was administered s.c. at doses of 0.0, 0.1, 0.32, 1.0, 3.2, 5.6 or 10.0 mg/kg to male and female rats (and 18.0 mg/kg was tested in females only), and then rats were immediately placed into one side of the apparatus for 30 min. Saline was administered before the second conditioning trial, after which rats were restricted to the opposite side of the apparatus for 30 min. On the third day, rats could explore the entire apparatus for 15 min, and time spent on each side, midline crosses, and paw thickness were recorded. Preliminary data show that, consistent with previous research, morphine treatment does not affect CFA‐induced inflammation. However, in both male and female rats, a single conditioning trial with morphine dose‐dependently induced place preference. Compared to control rats treated with intraplantar mineral oil, the peak place preference in CFA‐treated rats was shifted toward lower doses of morphine – however, morphine CPP varied significantly by the side of the apparatus that was paired with morphine, particularly in CFA‐treated rats. Specifically, greater place preference was observed when morphine was paired with the black wall/grid floor side than with the white wall/bar floor side. With approximately 75% of rats tested, no sex differences are apparent. These results suggest that rats with inflammatory pain experience rewarding effects from morphine differently than do healthy animals. Clinically, these results are of interest because they suggest that morphine's rewarding effects are not only affected by pain, but also by environment/context, particularly when subjects are in chronic pain.Support or Funding InformationSupported by The Psychopharmacology FundThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.