Antinociceptive tolerance to NSAIDs in the agranular insular cortex is mediated by opioid mechanism

Abstract

Several lines of investigations have shown that in some brain areas, in particular, in the midbrain periaqueductal gray matter, rostral ventromedial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of nonsteroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The agranular insular cortex (AIC) is a small region of the cerebral cortex located on the lateral area of the rat’s cerebral hemisphere that is involved in the perception and response to pain. In the present study, we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac, and xefocam microinjected into the AIC in rats. Male Wistar rats receiving NSAIDs into the AIC were tested for antinociception by tail-flick and hot plate tests. Treatment with each NSAID significantly enhanced the tail-flick and hot plate latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, ie, they developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented, and posttreatment naloxone abolished, the analgesic effects of the three NSAIDs in both behavioral assays. These findings support the notion that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

Brain-Wide Mapping of Afferent Inputs to Accumbens Nucleus Core Subdomains and Accumbens Nucleus Subnuclei

“…The NAc is important in many functions (Floresco, 2015), such as learning and memory (Li et al, 2018), reward processing (Carlezon and Thomas, 2009), addiction behavior, locomotor activity, stress-related aversion, liking (Castro et al, 2016), motivation (Castro and Bruchas, 2019), and sexual motivation (Everitt, 1990;Beny-Shefer et al, 2017). In addition, NAc dysfunction is associated with many mental disorders, including schizophrenia (Cotter et al, 2001), Huntington's disease (Albin et al, 1989), alcohol addiction and drug abuse (Volkow et al, 2007;Lobo et al, 2010;Pirkulashvili et al, 2017;Morales et al, 2019), Alzheimer's disease (Schliebs and Arendt, 2011;Nie et al, 2017), and depression (Nestler and Carlezon, 2006).…”

Predicting the efficacy of non-steroidal anti-inflammatory drugs in migraine using deep learning and three-dimensional T1-weighted images

“…Previous studies have reported that opioid receptor blockers injected into the core brain region of descending pain pathway could effectively reduce the analgesic effects of NSAIDs and have further suggested that NSAIDs act on the descending pain pathway via the endogenous opioid system to produce an antinociception effect. 36 , 37 , 38 Neuroimaging information may yield important representations in relation to treatment processes and outcomes. Although limited in number, some studies based on MRI techniques have revealed that changes in activity or morphology of the trigeminovascular system in patients with migraine were affected by different treatment modalities.…”

Agmatine Administration Effects on Equine Gastric Ulceration and Lameness

“…The lack of an effect of phenylbutazone after 29 days of administration in this study also suggests the development of drug tolerance. While this may not be well documented in horses, the development of anti-nociceptive tolerance to NSAIDs is documented in several species [48,49], and after 4 days of diclofenac, ketorolac, and lornoxicam administration in a rat nociceptive pain model [48]. Additionally, a recent meta-analysis of NSAIDs use by human knee OA patients revealed moderate pain reduction that peaked at 2 weeks, followed by diminished efficacy over 26 weeks [49].…”