Intracerebroventricular morphine produces antinociception by evoking gamma-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 (GABAergic) system is also suggested in supraspinal morphine antinociception. It has been reported that spinal GABAergic system contributes to 5-HT3 receptor-mediated 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 GABAA 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 (1 mm). In the behavioral study, intracerebroventricular morphine produced significant antinociception. Intrathecal administration of either GABAA receptor antagonist bicuculine or 3-tropanyl-indole-3-carboxylate methiodide but not vehicle reversed the morphine-induced antinociceptive effect.


CONCLUSIONS
Intracerebroventricular morphine evokes spinal GABA release via the activation of 5-HT3 receptors in the spinal cord, resulting in antinociceptive effect.
Kawamata
Tomoyuki
T
Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan. kawamata@sapmed.ac.jp
Omote
Keiichi
K
Toriyabe
Masaki
M
Kawamata
Mikito
M
Namiki
Akiyoshi
A
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000701:Analgesics, Opioid; D018756:GABA Antagonists; D009292:Narcotic Antagonists; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D001640:Bicuculline