Inhibition of COXI and not COX2 enzyme potentiates the opioid induced analgesia in rats

ABSTRACT

Opioids are widely used in the treatment of various types of pain and hyperalgesic states. However, opioid related side effects are well known and are representing a great challenge in using these drugs for the management of pain. A combined use of opioids with nonsteroidal anti-inflammatory drugs [NSAIDs] has been advocated in clinical practice to potentiate each other analgesic effect and to reduce the dose and related side effects of both drugs. Several studies on animal and human models have shown that such combination provides greater efficacy in pain relief. Reducing the doses of opioids used, due to the presence of N'SAIDs, ultimately reduces potential for side effects. It is unclear whether NSAIDs induces its opioid analgesic potentiating effect through inhibition of COX1 or COX2 enzymes. Both isoforms contribute to the inflammatory process, but COX2 is of considerable therapeutic interest as its induction, results in an enhanced formation of prostaglandins, during acute as well as chronic inflammation. It is generally assumed t hat NSAIDs anti-inflammatory and analgesic activity is mediated via COX2 inhibition. In contrast, it has been reported that the potencies of various NSAIDs to potentiate opioid induced presynaptic inhibitory effect nearly matched their inhibitory potencies at COX1. The present study was designed to study the effect of co-administration of the non selective COX inhibitor, indomethacin or diclofenac with pentazocine on pain relief and to compare it with the effect of its coadministration with the selective COX2 inhibitors, rofecoxib and meloxicam. Tail flick and hot plate assays were used asmodels o f central nociception. Non selective COX inhibitors, indomethacin and diclofenac potentiated the antinoceceptive effect of the opioid agonist pentazocine, an effect that was abolished by naloxone. The selective COX2 inhibitors, rofecoxib and meloxicam failed to modify the analgesic effect of pentazocine. These results suggest that analgesia potentiating effect of NSAIDs is mediated through inhibition of COX1 rather COX2 enzyme. The finding support a novel therapeutic intervention by which reduced doses of opioids can be used in the presence of NSAIDs that act preferentially on COX1 to produce effective pain relief with reduced side effects