Estudo sobre os mecanismos envolvidos na antinocicepção periférica induzida por tramadol em ratos

Abstract

Tramadol is a synthetic analgesic of central action that has shown promise, due to the low side effects on the respiratory, gastrointestinal system and little capacity to induce tolerance and additive potential, despite the main adverse effects nausea and vomiting. It is a drug that acts on moderate to severe pain by improving central pain modulation. Tramadol is inserted in the class of “atypical opioids”, since it has opioid and non-opioid mechanisms of action, thus, the mechanisms of action involve not only the binding to opioid receptors, but also the modulation of the central aminergic descending pathway. The pathways by which tramadol exerts local antinociception are still not well understood, so the present work was dedicated to studying the mechanisms by which tramadol could exert antinociception in an animal model. The opioidergic, cannabinoidergic, nitrergic, noradrenergic, serotonergic and dopaminergic systems were evaluated, as well as the participation of potassium channels in the peripheral antinociception of tramadol against prostaglandin-induced hyperalgesia E2. To measure the nociceptive threshold, the method of removing rat paws subjected to compression was used. The technique is based on the principle that PGE2 (2 µg) increases sensitivity to painful stimuli and that this increase is likely to be modified by drugs or procedures under test. One-way ANOVA analysis of variance was used, followed by Bonferroni's post-hoc for multiple comparisons as statistical analysis. To verify the participation of opioid and cannabinoid receptors in this event, we used the non-selective opioid antagonist naloxone (50 µg) and the cannabinoid receptor antagonists CB1 and CB2, AM251 (80 µg) and AM630 (100 µg), respectively, which were not able to reverse tramadol antinociception. When administering the non-selective inhibitor of the nitric oxide synthase enzymes, L-NOArg (24 and 48 µg), the reversal of antinociception was partial, which also occurred for the selective NOSe inhibitors, L-NIO (24, 48 µg) and NOSn, L-NPA (24.48 µg). The NOSi L-NIL inhibitor (24 µg) was unable to reverse antinociception. The inhibitor of the enzyme soluble guanylate cyclase ODQ reversed the peripheral antinociception of tramadol in a dose-dependent manner (25, 50 and 100 µg) and zaprinast (50 µg) was able to potentiate the antinociceptive effect of tramadol (60 µg). When evaluating the participation of channels for potassium, only glibenclamide was able to block tramadol antinociception, in a dose-dependent manner (20, 40 and 80 µg). On the other hand, the other channel blockers for potassium, tetraethylammonium (30 µg), which blocks voltage-dependent channels, dequalinium (50 µg) and paxillin (20 µg), which block channels activated by low and high conductance calcium, respectively , failed to alter antinociception of tramadol. The non-selective α2-adrenergic yohimbine receptor antagonist (20, 40 µg) partially reversed tramadol analgesia, while the selective α2C-adrenergic receptor antagonist rauwvolscine (10, 15, 20 µg) totally antagonized the analgesia. On the other hand, antagonists of the other α2-adrenergic receptor subtypes, α2A, α2B and α2D, BRL44480, imiloxane and RX821002 (20 µg), respectively, did not alter antinociception. As for the serotonergic system, the 5-HT1B, 5-HT1D and 5-HT3 receptor antagonists, isamoltane, BRL 15572 and ondasetron (100 ng, 1 and 10 µg), respectively, managed to block tramadol antinociception, but the antagonists of tramadol the other evaluated receptors, 5-HT2A and 5-HT7, ketanserin and SB269970 (10 µg), respectively, were not able to exert the same effect. As for the dopaminergic system, no evaluated receptor appears to be involved in the effect of tramadol. D2, D3 and D4 receptor antagonists, remoxipride (4.20 µg), U99194 (32 µg) and L-745.870 (32 µg), respectively, were evaluated. Our data suggest, for the first time, the peripheral antinociceptive action induced by tramadol when administered in a model of PGE2-induced hyperalgesia, and that this effect should involve the α2C-adrenergic receptors, the 5-HT1B, 5-HT1D and 5-HT3 serotonergic receptors. , in addition to the nitrergic system and ATP-sensitive potassium channels.