An Overview of Antinociceptive Tolerance to Non-steroidal Anti-inflammatory Drugs

Abstract

Purpose of Review: One of the vital functions of the nervous system is to provide information about the threat of injury. The sensation of pain by its inherent aversive nature, contributes to this function. The mainstay of medical pain therapy remains drugs that have been around for decades, like opiates and non-opioid drugs. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic administration of non-opioid, non-steroidal anti-inflammatory drugs (NSAIDs) induces antinociception with some effects of tolerance. In this review, we report that repeated microinjections of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. Conclusions: Presented data show that repeated microinjections of NSAIDs into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus induce antinociception and then exhibit tolerance. These findings strongly support the suggestion of endogenous opioid system involvement in NSAIDs antinociception, as it is blocked by an opioid antagonist naloxone. Moreover, the descending pain-control system, the periaqueductal grey – rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system.