The central nucleus of amygdala is involved in tolerance to the antinociceptive effect of NSAIDs

Aim: Repeated microinjections of non-opioid analgesics into the midbrain periaqueductal gray matter and rostral ventro-medial medulla induce antinociception with development of tolerance. Antinociception following systemic administration of non-steroidal anti-inflammatory drugs (N SAIDs) also exhibit tolerance. Presently our aim was to investigate the development of tolerance to the antinociceptive effects of NSAIDs analgine, ketorolac, and xefocam microinjected into central nucleus of amygdala (Ce) in rats. Methods: Under anesthesia with thiopental a stainless steel guide cannula was stereotaxically implanted unilaterally or bilaterally into the Ce using stereotaxic atlas coordinates, and anchored to the cranium by dental cement. Five days after surgery, 3 μl of these NSAIDs were injected via the injection cannula while the rat was gently restrained. Twenty min post microinjection, i.e. 10-min before the peak of the drugs’ effect is normally reached, animals were tested with tail flick (TF) and hot plate (HP) tests. On the 5th experimental day all animals received a Ce microinjection of morphine. Results: Daily microinjection of NSAIDs into the Ce unior bilaterally, produced antinociception with development of complete tolerance over a 5-day period. Following the treatment period, morphine microinjection into the Ce failed to elicit antinociception, indicating cross-tolerance to the antinociceptive effect of N SAIDs. In other words, the “non-opioid tolerant” rats showed cross-tolerance to morphine. Conclusions: Our data confirmed the suggestion that NSAIDs interact with endogenous opioid systems, which likely play a key role in the development of tolerance to the antinociceptive effects of NSA IDs.