RESUMEN
It has already been shown that serotonin can release endocannabinoids at the spinal cord level, culminating in inhibition of the dorsal horn. At the peripheral level, cannabinoid receptors modulate primary afferent neurons by inhibiting calcium conductance and increasing potassium conductance. Studies have shown that after the activation of opioid receptors and cannabinoids, there is also the activation of the NO/cGMP/KATP pathway, inducing cellular hyperpolarization. In this study, we evaluated the participation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway in the peripheral antinociceptive effect of serotonin. The paw pressure test of mice was used in animals that had their sensitivity to pain increased due to an intraplantar injection of PGE2 (2 µg). Serotonin (250 ng/paw), administered locally in the right hind paw, induced antinociceptive effect. CB1 and CB2 cannabinoid receptors antagonists, AM251 (20, 40 and 80 µg) and AM630 (25, 50 and 100 µg), respectively, reversed the serotonin-induced antinociceptive effect. MAFP (0.5 µg), an inhibitor of the FAAH enzyme that degrades anandamide, and JZL184 (3.75 µg), an inhibitor of the enzyme MAGL that degrades 2-AG, as well as the VDM11 (2.5 µg) inhibitor of anandamide reuptake, potentiated the antinociceptive effect induced by a low dose (62. 5 ng) of serotonin. In the evaluation of the participation of the NO/cGMP/KATP pathway, the antinociceptive effect of serotonin was reversed by the administration of the non-selective inhibitor of NOS isoforms L-NOarg (12.5, 25 and 50 µg) and by the selective inhibitor for the neuronal isoform LNPA (24 µg), as well as by the soluble guanylate cyclase inhibitor ODQ (25, 50 and 100 µg). Among potassium channel blockers, only Glibenclamide (20, 40 and 80 µg), an ATP-sensitive potassium channel blocker, reversed the effect of serotonin. In addition, intraplantar administration of serotonin (250 ng) was shown to induce a significant increase in nitrite levels in the homogenate of the plantar surface of the paw of mice. Taken together, these data suggest that the antinociceptive effect of serotonin occurs by activation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway.
Asunto(s)
Cannabinoides , Ratones , Animales , Cannabinoides/metabolismo , Analgésicos/farmacología , Serotonina/farmacología , Bloqueadores de los Canales de Potasio , Receptores de Cannabinoides , Adenosina Trifosfato , Hiperalgesia/metabolismoRESUMEN
Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1ß and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.