RESUMO
Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.
Assuntos
Norepinefrina , Receptores de Serotonina , Antagonistas da Serotonina , Serotonina , Animais , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Masculino , Receptores de Serotonina/metabolismo , Dinoprostona/metabolismo , Citalopram/farmacologia , Nociceptividade/efeitos dos fármacos , Analgésicos/farmacologia , Ondansetron/farmacologia , Ketanserina/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
BACKGROUND: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. METHODS: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. RESULTS: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. CONCLUSION: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.
Assuntos
Analgésicos , Canabidiol , Classe Ib de Fosfatidilinositol 3-Quinase , Canais KATP , Neuralgia , Óxido Nítrico Sintase Tipo I , Óxido Nítrico , Transdução de Sinais , Animais , Canabidiol/farmacologia , Canais KATP/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Analgésicos/farmacologia , AnalgesiaRESUMO
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.
Assuntos
Canabinoides , Camundongos , Animais , Canabinoides/metabolismo , Analgésicos/farmacologia , Serotonina/farmacologia , Bloqueadores dos Canais de Potássio , Receptores de Canabinoides , Trifosfato de Adenosina , Hiperalgesia/metabolismoRESUMO
Cannabidiol (CBD) is the most abundant non-psychoactive component found in plants of the genus Cannabis. Its analgesic effect for the treatment of neuropathy has been widely studied. However, little is known about its effects in the acute treatment when Cannabidiol is administered peripherally. Because of that, this research was aimed to evaluate the antinociceptive effects of the CBD when administered peripherally for the treatment of acute neuropathic pain and check the involvement of the 5-HT1A and the TRPV1 receptors in this event. Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mouse paw. The technique used proved to be efficient to induce neuropathy, and the CBD (5, 10 and 30 µg/paw) induced the antinociception in a dosage-dependent manner. The dosage used that induced a more potent effect (30 µg/paw), did not induce a systemic response, as demonstrated by both the motor coordination assessment test (RotaRod) and the antinociceptive effect restricted to the paw treated with CBD. The administration of NAN-190 (10 µg/paw), a selective 5-HT1A receptor antagonist, and SB-366791 (16 µg/paw), a selective TRPV1 antagonist, partially reversed the CBD-induced antinociception. The results of the research suggest that the CBD produces the peripheral antinociception during the acute treatment of the neuropathic pain and it partially involved the participation of the 5-HT1A and TRPV1 receptors.
Assuntos
Canabidiol , Neuralgia , Camundongos , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Serotonina , Neuralgia/tratamento farmacológico , Modelos Animais de Doenças , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Receptor 5-HT1A de Serotonina , Canais de Cátion TRPVRESUMO
BACKGROUND: Curcumin is one of the compounds present in plants of the genus Curcuma sp., being very used not only as condiment but also with medicinal purposes. As an analgesic, papers highlight the efficacy of curcumin in the treatment of various types of pain. AIMS: In this study we evaluated the peripheral antinociceptive effect of curcumin and by which mechanisms this effect is induced. MAIN METHODS: The mice paw pressure test was used on animals which had increased pain sensitivity by intraplantar injection of carrageenan. All the drugs were administered in the right hind paw. KEY FINDINGS: Curcumin was administered to the right hind paw animals induced antinociceptive effect. Non -selective antagonist of opioid receptors naloxone reverted the antinociceptive effect induced by curcumin. Selective antagonists for µ, δ and κ opioid receptors clocinnamox, naltrindole and nor- binaltorphimine, respectively, reverted the antinociceptive effect induced by curcumin. Bestatin, enkephalinases inhibitor that degrade peptides opioids, did not change the nociceptive response. Selective antagonists for CB1 and CB2 cannabinoid receptors, AM251 and AM630, respectively, reversed the antinociceptive effect induced by curcumin. The MAFP inhibitor of the enzyme FAAH which breaks down anandamide, JZL184, enzyme inhibitor MAGL which breaks down the 2-AG, as well as the VDM11 anandamide reuptake inhibitor potentiated the antinociceptive effect of curcumin. SIGNIFICANCE: These results suggest that curcumin possibly peripheral antinociception induced by opioid and cannabinoid systems activation and possibly for endocannabinoids and opioids release.