Background & Aims
Pain sensation is a common experience and its treatment, especially in chronic states, remains a medical and social problem. Emotional distress is an intrinsic and the most disruptive and undesirable feature of pain behavior. Therefore, pain perception depends on the activation of mechanisms that control emotional functions in brain limbic areas such as the hypothalamus, amygdala, hippocampus, and insular and cingulate cortices. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics. However, a few recent studies have demonstrated that these non-opioid drugs in the case of prolonged use, elicit the opioid-like effect, tolerance, which alongside the drug withdrawal syndrome may entail serious adverse effects. Here are collected data from the study of brain mechanisms of non-opioid-induced antinociceptive tolerance to NSAIDs [1].
Methods
The study was carried out on adult male rats. Under anesthesia with intramuscular administration of ketamine, stainless steel guide cannula was stereotaxically implanted bilaterally into the brain limbic areas for injection NSAIDs (diclofenac, ketorolac, ketoprofen, and lornoxicam) and pre- or post-administration of a combined opioid receptor antagonist (naloxone, or CTOP) and cannabinoid receptor (CB1) antagonist (AM-251). We measured nociceptive thermal paw withdrawal latencies (Hargreaves test) and mechanical thresholds (electronic von Frey test) in experimental and control (saline) rats.
Results
Microinjections of widely used non-opioid, NSAID analgesics diclofenac, ketoprofen, ketorolac, and lornoxicam into pain matrix key structures of brain limbic areas, such as the rostral part of the anterior cingulate cortex, agranular insular cortex, and central nucleus of amygdala of rats induced antinociception. When administered repeatedly, tolerance developed to the antinociceptive effects of these drugs. Pre- or post-treatment with opioid receptor antagonists, naloxone and CTOP as well as cannabinoid CB1 receptor antagonist AM-251, separately or in combination in the CeA, prevented or abolished antinociceptive effects of these non-opioid analgesics.
Conclusions
Here we confirmed the concept that antinociception and the development of tolerance to NSAIDs are mediated via endogenous opioid and cannabinoid systems involving the descending pain modulatory circuits attenuating pain behavior in rats – defensive paw withdrawal reflexes at the spinal cord level.
References
1. Tsagareli N., Tsiklauri N., Tsagareli M.G. (2021) Antinociceptive Tolerance to NSAIDs in Brain Limbic Areas: Role of Endogenous Opioid and Cannabinoid Systems. New York: Nova.
Acknowledgment. The work was partially supported by a grant from the Shota Rustaveli National Science Foundation of Georgia (SRNSFG, # FR-21/2322).
Presenting Author
Merab G. Tsagareli
Poster Authors
Merab Tsagareli
PhD, DSc
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
Lead Author
Natia Tsagareli
PhD
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
Lead Author
Gulnaz Gurtskaia
PhD
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
Lead Author
Ivliane Nozadze
PhD
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
Lead Author
Gulnara Gedevanishvili
PhD
Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
Lead Author
Topics
- Models: Acute Pain