The Effects of Intrathecal Adenosine A1 Receptor Agonists (R-PIA) on the Morphine Tolerance in a Rat Model of Postoperative Pain

Analgesic tolerance to opioids has been described in both experimental and clinical conditions, which may limit their clinical utility. This study investigated the effects of intrathecal adenosine A1 receptor agonist (R-PIA) on spinal morphine tolerance. Methods: SD rats were given intrathecal injections of saline 10μl, R-PIA 10μg, morphine 10μg, or R-PIA plus morphine combinations for 7 days (R-PIA given for days 1-7; days 1-3; or days 5-7). Antiallodynic testing using von Frey filaments was carried out before and 30 minutes after the drug injection. On day 8, an antiallodynic dose-response curve was constructed and the 50% effective dose (ED50) for morphine (given alone) was calculated for each study group. Results: The coinjection group of R-PIA with morphine blocked the development of tolerance, as shown by the preservation of morphine antiallodynia over 7 days the concomitant decrease in the ED50 values on day 8, compared with the morphine-alone group. Although additive analgesia over days 1-7 cannot be ruled out, the reductions of the ED50 in the R-PIA and morphine combination group suggest some suppression of tolerance. Conclusions: These results suggest that intrathecal R-PIA prevents the development of spinal opioid tolerance. Future studies will be needed to examine the respective roles of supraspinal and peripheral sites of R-PIA and morphine interaction, and to investigate the mechanisms underlying the action of R-PIA on opioid tolerance.