Intracerebroventricular morphine produces antinociception by evoking γ-aminobutyric acid release through activation of 5-hydroxytryptamine 3 receptors in the spinal cord

Background: It has been generally considered that supraspinal morphine activates the serotonergic descending inhibitory system and releases serotonin (5-hydroxytryptamine [5-HT]) in the spinal cord, producing antinociception through activation of 5-HT receptors. The involvement of a spinal gamma-aminobutyric acid-mediated (G-AR-kergic) system is also suggested In supraspinal morphine antinociception. It has been reported that spinal GABAcrgic system contributes to 5-HT3 receptor-niediated antinociception. in this study, the authors investigated the contribution of spinal 5-HT3 receptor and the GABAergic system in the intracerebroventricular morphine-induced antinociception. Methods: Male Sprague-Dawley rats were used. Using the spinal microdialysis method, concentrations of 5-HT and GABA were measured after intracerebroventricular morphine administration. The effect of intracerebroventricular naloxone or spinal perfusion of a selective 5-HT3 receptor antagonist 3-tropanyl-indole-3-carboxylate methiodide on the spinal release of GABA after intracerebroventricular morphine administration was also examined. In the behavioral study, involvement of 5-HT3 receptors or GABA(A) receptors in the intracerebroventricular morphine-induced antinociceptive effect was investigated using the tail-flick test. Results: Intracerebroventricular morphine (40 nmol) significantly increased spinal GABA and 5-HT release. Evoked spinal GABA release was reversed by intracerebroventricular naloxone (40 nmol) or spinal perfusion of 3-tropanyl-indole-3-carboxylate methiodide (I mM). In the behavioral study, intracerebroventricular morphine produced significant antinociception. Intrathecal administration of either GABA(A) receptor antagonist bicucline or 3-tropanyl-indole-3-carboxylate methiodide but not vehicle reversed the niorphine-induced antinociceptive effect. Conclusion: Intracerebroventricular morphine evokes spinal GABA release via the activation of 5-HT3 receptors in the spinal cord, resulting in anti-nociceptive effect.