Involvement of Nitric Oxide and ATP‐Sensitive Potassium Channels in the Peripheral Antinoceptive Action of a Tramadol–Dexketoprofen Combination in the Formalin Test

Abstract

Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate pathway and ATP-sensitive K(+) channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin-injured mouse paw and the antinociceptive effect evaluated. ED50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l-NG-nitroarginine methyl ester and 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, or the ATP-sensitive K(+) channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol-dexketoprofen combination, suggesting that NO and ATP-sensitive K(+) channels were involved.

Antinociceptive local effect of the combination of dexketoprofen trometamol and chlorhexidine gluconate in a formalin test: an additive effect

“…This work confirmed the antinociceptive effect of DXT when is locally administered in the formalin test, using the 50% effective dose of DXT previously reported by Isiordia et al (2014). The local use of NSAID´S can provide acceptable pain relief, commonly reported in acute conditions.…”

Non-steroidal Anti-inflammatory Drugs in Tonic, Phasic and Inflammatory Mouse Models

“…Thereby, among the evidences has been included their interaction with monoaminergic, nitric oxide, endocannabinoids, serotonergic and cholinergic systems and endogenous opioid pathway [13][14][15][16].…”

Efficacy of mepivacaine–tramadol combination on the success of inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis: a randomized clinical trial

“…Similarly, it has been proposed that tramadol exerts an antinociceptive effect that is related to the voltage‐dependent potassium channels, which may play an important role in modulating pain stimuli (Yalcin & Aksu , Isiordia‐Espinoza et al . ). Another possible explanation is that in the presence of intracellular calcium, its antinociceptive effect is improved; however, more studies are needed to understand the underlying mechanisms (Mert et al .…”

“…Other possible mechanisms involved are the agonistic activity over local opioid receptors in the peripheral ends of myelinated and unmyelinated fibres (Stein , Sawynok ), antinociceptive mechanisms related to the voltage‐dependent potassium channels (Yalcin & Aksu , Isiordia‐Espinoza et al . ) and its possible agonism over transient receptor potential vallinoid‐1 (TRVP‐1), causing not only local analgesia but a transient burning sensation in the skin (Marincsak et al . ).…”