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

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

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

“…The data reported in this study demonstrate that microinjection of commonly used NSAIDs, diclofenac, ketorolac and xefocam into the rostral part of ACC induces antinociception. These findings are in resemblance with the results of our and other colleagues’ previous investigations in an acute pain model with TF and HP tests, and in which metamizol, xefocam, ketorolac or lysine-acetylsalicylate were given systemically or microinjected into the PAG [ 10 , 11 , 16 – 18 , 25 ], into the CeA [ 13 , 21 ], and the NRM [ 13 , 20 , 26 ]. In the other investigation, responses of spinal dorsal horn wide-dynamic range neurons of rats to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous metamizol [ 27 ].…”

“…in juvenile and adult rats in models of acute pain [ 17 , 18 ]. We have also revealed that repeated microinjections of these non-opioids into the dorsal hippocampus (DH), the nucleus raphe magnus (NRM), and the central nucleus of amygdala (CeA), induce antinociception and the effects of tolerance and cross-tolerance to morphine [ 13 , 14 , 19 – 21 ]. These findings strongly support the suggestion of endogenous opioids involvement in NSAIDs antinociception and tolerance in the descending pain-control system [ 13 , 22 ].…”

Antinociceptive tolerance to NSAIDs microinjected into dorsal hippocampus

“…Importantly, repeated microinjections of NSAIDs into the DH resulted in a progressive decrease in antinociceptive effectiveness, i.e. induced tolerance similar to that observed with intra-PAG, CeA and NRM injections [ 11 , 12 , 14 - 17 ], and reminiscent of the effect of opiates. For example, it has recently been shown that repeated intrathecal injections of a selective delta opioid receptor (DOPR) agonists deltorphin II or morphine induce tolerance effects on antihyperalgesic and antinociceptive responses in rodents [ 26 ].…”

Is Hippocampus Susceptible to Antinociceptive Tolerance to NSAIDs Like the Periaqueductal Grey?

“…In the other experiments in rats, responses of spinal dorsal horn wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous NSAID dipyrone (metamizole) [30]. Importantly, repeated microinjections of NSAIDs into the DH resulted in a progressive decrease in antinociceptive effectiveness, that is, induced tolerance similar to that observed with intra-PAG, CeA, and NRM injections [16, 17, 19–22], and reminiscent of the effect of opiates.…”