Nitric Oxide and Opioids Involvement in Isobolographic Nsaids Antinociception

Abstract

Different NSAIDs are used as antinociceptive in various analgesic assays, among which should be mentioned: ibuprofen, ketorolac , ketoprofen, meloxicam , paracetamol and others. It has been shown that NSAIDs possess antinociceptive activity by blocking cyclooxygenase enzymes (COXs). The present study was designed to evaluate the possible involvement of the nitridergic pathway due to L-NAME and the opioidergic route by NTX in the antinoception induced by NSAIDs using a murine pain model the tail flick test in an automatic tail flick algesiometer. The antinociception was evaluated by means of isobolographic analysis. The interaction between the combination of NSAIDs, via i.p., on basis of their ED₂₅, demonstrated that the coadministration of the drugs were synergistic with the exception of the lack of effect in combination of meloxicam with ibuprofen and with ketorolac, since the result was additive. These data validate that the NSAIDs administered alone or in combinations produce antinociception in which other mechanisms of action must be added to the simple inhibition of COXs. In addition, the pretreatment of the mice with L-NAME and NTX does not change previous isobolographic parameters of the mixture of NSAIDs.

Key words

NSAIDs - isobolographic analysis - serotonin - opioids - L-NAME - naltrexone

• References

• 1 acchi S B, Palumbo P, Sponta A. et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 2012; 11: 52-64
• 2 Chandrasekharan NV, Dai H, Roos KL. et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning,structure, and expression. Proc Natl Acad Sci USA 2002; 99: 13926- 13931
• 3 Rouzer CA, Marnett LJ. Cyclooxygenases: Structural and functional insights. J Lipid Res 2009; 50 (Suppl) S29-S34
• 4 Patrignani P, Patrono C. Cyclooxygenase inhibitors: From pharmacology to clinical read-outs. Biochim Biophys Acta 2015; 1851: 422-432
• 5 Praveen Rao PN, Knaus EE. Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond. J Pharm Pharmaceut Sci (www. Csps Canada.org) 2008; 11: 81-110
• 6 Zhou WZ, Zhao TY, Wang ZY. et al. Synergistic antinociception between ZC88, an N-type voltage-dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain. Eur J Pain 2019; 23: 46-56
• 7 Zapata-Morales JR, Aragon-Martinez OH, Adriana Soto-Castro T. et al. Isobolographic analysis of the interaction between tapentadol and ketorolac in a mouse model of visceral pain. Drug Dev Res 2016; 77: 187-191
• 8 Dogrul A, Gülmez SE, Deveci MS. et al. The local antinociceptive actions of nonsteroidal antiinflammatory drugs in the mouse radiant heat tail-flick test. Anesth Analg 2007; 104: 927-935
• 9 Girard P, Verniers D, Coppé MC. et al. Nefopam and ketoprofen synergy in rodent models of antinociception. Eur J Pharmacol 2008; 584: 263-271
• 10 Miranda HF, Prieto JC, Pinardi G. Spinal synergy between nonselective cyclooxygenase inhibitors and morphine antinociception in mice. Brain Res 2005; 1049: 165-170
• 11 Gonzalez C, Zegpi C, Noriega V. et al. Synergism between dexketoprofen and meloxicam in an orofacial formalin test was not modified by opioid antagonists. Pharmacol Rep 2011; 63: 433-440
• 12 Dudhgaonkar SP, Tandan SK, Kumar D. et al. Synergistic interaction between meloxicam and aminoguanidine in formalin-induced nociception in mice. Eur J Pain 2008; 12: 321-328
• 13 Miranda HF, Puig MM, Prieto JC. et al. Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain. Pain 2006; 121: 22-28
• 14 Da Silva DPB, Florentino IF, da Silva DM. et al. Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization. Inflammopharmacology 2018; 26: 1189-1206
• 15 Dableh LJ, Henry JL. The selective neuronal nitric oxide synthase inhibitor 7-nitroindazole has acute analgesic but not cumulative effects in a rat model of peripheral neuropathy. Journal of Pain Research 2011; 4: 85-90
• 16 Salvemini D. Regulation of cyclooxygenase enzymes by nitric oxide. Cell Mol Life Sci 1997; 53: 576-582
• 17 Cuzzocrea S, Salvemini D. Molecular mechanisms involved in the reciprocal regulation of cyclooxygenase and nitric oxide synthase enzymes. Kidney Int 2007; 71: 290-297
• 18 Kim SF. The role of nitric oxide in prostaglandin biology; update. Nitric Oxide 2011; 25: 255-264
• 19 Tamaki J, Maeda M. et al. Biological implications of coeruleospinal inhibition of nociceptive processing in the spinal cord. Frontiers in Integrative. Neuroscience 2012; 6: 1-10
• 20 Nozadze I, Tsiklauri N, Gurtskaia G. et al. Opioid sensitivity of nucleus raphe magnus ater analgesia by nonsteroidal anti-inflammatory drugs. Georgian Med News 2011; 190: 50-55
• 21 Tsagareli MG, Tsiklauri N, Nozadze I. et al. Tolerance effects of non-steroidal anti-inflammatory drugs microinjected into central amygdala, periaqueductal grey, and nucleus raphe: Possible cellular mechanism. Neural Regen Res 2012; 7: 1029-1039
• 22 Tsagareli N, Tsiklauri N, Tsagareli M. et al. Naloxone and ctop block nsaids-induced antinociception in anterior cingulate cortex of rats. Georgian Med News 2019; 286: 116-122
• 23 Hamza M, Dionne RA. Mechanisms of non-opioids analgesics beyond cyclooxygenase enzyme inhibition. Curr Mol Pharmacol 2009; 2: 1.14
• 24 Dwivedi AK, Gurjar V, Kumar S. et al. Molecular basis for nonspecific of nonsteroidal anti-inflammatory drugs (NSAIDs). Drug Discov Today 2015; 20: 863-873
• 25 Bujalska M. Effect of cyclooxygenase and NO synthase inhibitors administered centrally on antinociceptive action of acetaminophen (Part II). Pol J Pharmacol 2003; 55: 1001-1011
• 26 Granados-Soto V, Flores-Murrieta FJ, Castaneda-Hernandez G. et al. Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac. Eur J Pharmacol 1995; 277: 281-284
• 27 Aguirre-Bañuelos PP, Granados-Soto VV. Evidence for the participation of the nitric oxide-cyclic GMP pathway in the antinociceptive action of meloxicam in the formalin test. Eur J Pharmacol 2000; 395: 9-13
• 28 Prado WA, Schiavon VF, Cunha FQ. Dual effect of local application of nitric oxide donors in a model of incision pain in rats. Eur J Pharmacol 2002; 441: 57-65
• 29 Schumacher M, Basbaum A, Ramana N. Opioid Agonists & Antagonists. In Basic & Clinical Pharmacology & Toxicology. 13^th ed. Katzung B, Trevor A. Eds. Wiley; Hoboken, NJ, USA: 2014. p 531
• 30 Trofimovitch D, Baumrucker SJ. Pharmacology Update: Low- dose naltrexone as a possible nonopioid modality for some chronic, nonmalignant pain syndromes. Am J Hosp Palliat Care 2019; DOI: 0.1177/1049909119838974.
• 31 Rezende RM, Dos Reis WG, Duarte ID. et al. The analgesic actions of centrally administered celecoxib are mediated by endogenous opioids. Pain 2009; 142: 94-100
• 32 Déciga-Campos M, Mata R. Rivero-Cruz. Antinociceptive pharmacological profile of Dysphania graveolens in mouse. Biomed Pharmacother 2017; 89: 933-938
• 33 AMS Brito, Godin AM, PSA Augusto. et al. Antiallodynic activity of leflunomide is partially inhibited by naltrexone and glibenclamide and associated with reduced production of TNF-α and CXCL-1. Eur J Pharmacol 2018; 818: 17-25