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.

Non-opioid Analgesics and the Endocannabinoid System

“…When administered intravenously, dipyrone also causes anti-nociception by activating the endogenous opioid system ( 81 ). Other than its interaction with endogenous opioids, dipyrone is suggested to possess (weak) antinociceptive activity by classical COX inhibition ( 82 ), and by activation of the L-arginine-nitric oxide pathway and subsequent K ATP channel opening ( 83 ), although there are some opposite findings ( 84 , 85 ).…”

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“…This test is commonly accepted to assess the activities of opioids administrated alone . In other experiments, NSAIDs injected intrathecally exhibited more effective potency than systemic administration, and NSAIDs demonstrated distinct potencies in the tail-flick test (Miranda et al , 2019b.…”