RESUMO
Mygalin, a diacylspermidine that is naturally found in the hemolymph of the spider Acanthoscurria gomesiana, is of interest for development as a potential analgesic. Previous studies have shown that acylpolyamines modulate glutamatergic receptors with the potential to alter pain pathways. This study aimed to evaluate the effects of mygalin on acute and chronic pain in rodents. For evaluation of acute pain, Wistar rats were subjected to tail-flick and hot-plate nociceptive tests. For the evaluation of chronic neuropathic pain, a partial ligation of the sciatic nerve was performed and, 21 days later, animals were examined in hot-plate, tail-flick, acetone, and von Frey tests. Either Mygalin or vehicle was microinjected in the dorsal raphe nucleus (DRN) before the tests. Another group was pretreated with selective antagonists of glutamate receptors (LY 235959, MK-801, CNQX, and NBQX). Mygalin decreases nociceptive thresholds on both acute and chronic neuropathic pain models in all the tests performed. The lowest dose of mygalin yielded the most effective nociception, showing an increase of 63% of the nociceptive threshold of animals with neuropathic chronic pain. In conclusion, mygalin microinjection in the DRN results in antinociceptive effect in models of neuropathic pain, suggesting that acylpolyamines and their derivatives, such as this diacylspermidine, could be pursued for the treatment of neuropathic pain and development of selective analgesics.
Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/administração & dosagem , Dor Crônica/tratamento farmacológico , Núcleo Dorsal da Rafe/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Espermidina/análogos & derivados , Aranhas/metabolismo , Medicamentos Sintéticos/administração & dosagem , Animais , Modelos Animais de Doenças , Hemolinfa/química , Masculino , Microinjeções/métodos , Ratos , Ratos Wistar , Espermidina/administração & dosagem , Resultado do TratamentoRESUMO
The blockade of GABA-mediated Cl(-) influx with pentylenetetrazol (PTZ) was used in the present work to induce seizures in Rattus norvegicus. The aim of this work was to study the involvement of monoamines in the antinociception induced by convulsions elicited by peripheral administration of PTZ (64 mg/kg). The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the postictal period. Peripheral administration of methysergide (0.5, 1, 2, and 3 mg/kg) caused a significant decrease in the TFL in seizing animals, as compared to controls, in all postictal periods studied. These findings were corroborated by the pretreatment with ketanserin, a 5-HT(2A/2C)-serotonergic/alpha(1)-noradrenergic receptors antagonist, at the same doses. Peripheral administration of yohimbine (0.5, 1, 2, and 3 mg/kg), alpha(2)-noradrenergic antagonist, also decreased the postictal analgesia either at initial or more terminal periods of the postictal analgesia. These data were corroborated with peripheral administrations of propranolol, a beta-noradrenergic receptor blocker that caused a decrease in the postictal analgesia consistently in later stages (after the first 20-min post-tonic-clonic convulsive reactions) of the post-seizure analgesia, except for the highest dose. These results indicate that monoamines may be involved in the postictal analgesia. The blockade of 5-HT(2A/2C)-serotoninergic, alpha(1)-noradrenergic, or alpha(2)-noradrenergic receptors before tonic clonic seizure-induced analgesia antagonized the increase in the nociceptive threshold caused by seizures in initial steps of the temporal antinociceptive curve, as compared to the blockade of beta-noradrenergic ones. These findings suggest that the recruitment of alpha-noradrenergic receptor and serotonergic receptors was made immediately after convulsions and in other initial periods of the postictal analgesia, as compared to the involvement of beta-noradrenergic receptor. Neurochemical lesions of the locus coeruleus (LC) and neuronal damage of the dorsal raphe nucleus induced a significant decrease of the postictal analgesia, suggesting the involvement of these nuclei in this antinociceptive process. The functional neuroanatomical study of the neural link between the mesencephalic tectum and nuclei of the central pain inhibitory system showed evidence for the interconnection between superior colliculus, both dorsal and ventral periaqueductal gray matter (PAG), and inferior colliculus. Defensive substrates of the inferior colliculus, also involved with wild running and epilepsy, send inputs toward dorsal raphe nucleus and locus coeruleus. Since these nuclei are rich in monoamines and send neural connections toward other monoaminergic nuclei of the brainstem involved with the control of the nociceptive inputs in the dorsal horn of the spinal cord, the present results offer a neuroanatomical and psychopharmacological basis for the antinociceptive processes following tonic-clonic seizures.