Abstract
Aim: Repeated microinjections of non-opioid an-algesics into the midbrain periaqueductal gray matter and rostral ventro-medial medulla induce antinociception with development of tolerance. Antinociception following systemic administra-tion 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 cen-tral nucleus of amygdala (Ce) in rats. Methods: Under anesthesia with thiopental a stainless steel guide cannula was stereotaxically implanted uni- laterally or bilaterally into the Ce using stereo-taxic atlas coordinates, and anchored to the cra- nium by dental cement. Five days after surgery, 3 µl of these NSAIDs were injected via the injec-tion cannula while the rat was gently restrained. Twenty min post microinjection, i.e. 10-min be-fore the peak of the drugs’ effect is normally rea- ched, animals were tested with tail flick (TF) and hot plate (HP) tests. On the 5th experimental day all animals received a Ce microinjection of mor-phine. Results: Daily microinjection of NSAIDs into the Ce uni- or bilaterally, produced antino-ciception with development of complete toler-ance over a 5-day period. Following the treat-ment period, morphine microinjection into the Ce failed to elicit antinociception, indicating cro- ss-tolerance to the antinociceptive effect of N SAIDs. In other words, the “non-opioid tolerant” rats showed cross-tolerance to morphine. Con-clusions: 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.
Highlights
Microinjection of non-opioid analgesics metamizol, and lysine-acetylsalicylate (LASA) into certain brain areas, including the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM), produces antinociception with development of some degree of tolerance [1,2,3,4]
The present study reports that microinjection of analgine, ketorolac, and xefocam into the central nucleus of amygdala (Ce) of rats elicits antinociception with the development of tolerance
On successive days, microinjection of each non-steroidal anti-inflammatory drugs (NSAIDs) had a progressively weaker antinociceptive effect such that on the fourth and/or fifth experimental days the tail flick (TF) and hot plate (HP) latencies were not significantly different compared to saline injections
Summary
Microinjection of non-opioid analgesics metamizol, and lysine-acetylsalicylate (LASA) into certain brain areas, including the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM), produces antinociception with development of some degree of tolerance [1,2,3,4]. We have observed tolerance to the antinociceptive effects of analgine (metamizol), ketorolac, and xefocam administered systemically [5,6,7]. These studies are consistent with the possibility that endogenous opioidergic mechanisms associated with descending pain modulation may partly mediate the tolerance observed with non-steroidal anti-inflammatory drugs (NSAIDs) [8]. Cortical afferents to the amygdala largely target its basolateral component. The Ce receives nociceptive input, both directly from the spinal cord, and indirectly via a large projection from the dorsal horn to the parabrachial nucleus [14,15]. The Ce is an integral component of the endogenous pain-modulatory circuit and is critical for systemic morphine-induced suppression of spinal nociceptive reflexes [16]
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