The Effects of Tramadol and Its Metabolite on Glycine, ??-Aminobutyric AcidA, and N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes

Abstract

We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadol's action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid(A) (GABA(A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA(A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA(A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations.

Endogenous opioids participation in the effect of Rosmarinus officinalis L. in the visceral, inflammatory and gout arthritis nociception in rodents (Participación de los opioides endógenos en el efecto de Rosmarinus officinalis L. en la nocicepción visceral, inflamatoria y artritis gotosa en roedores)

“…However, it has been described that tramadol produces analgesic activity by modulation of monoamines like noradrenaline and serotonin, but also by GABAergic neurotransmission. 33 Moreover, it is considered that mechanisms of action of tramadol involve a partial action through µ-opioid receptors, 34 which is in accord with our results because the presence of naloxone partially reverted the antinociceptive effect of this analgesic drug in all models experienced in our study.…”

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

“…The exact mechanism of tramadol in induction of seizure remains to be elucidated yet. Research indicates that in high concentrations tramadol exerts an inhibitory effect on gammaaminobutyric acid (GABA) receptors [12,13]. Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14].…”

Safety and efficacy of tramadol hydrochloride on treatment of premature ejaculation

“…49,50 Although the mechanism by which tramadol delays ejaculation has not been elucidated, numerous laboratory studies have shown that tramadol acts as a mild m-opioid agonist, 23 N-methyl-D-aspartate receptor antagonist. 53 5-hydroxytryptamine type 2C receptor antagonist, 54 5-nicotinic acetylcholine receptor antagonist, 55 M1 and M3 muscarinic acetylcholine receptor antagonist, 56 and a serotonin and norepinephrine modulator. 23 It is possible that one or a combination of these effects leads to a delay in ejaculation.…”