naloxone and gaboxadol

The nuclei comprising the neuronal network for audiogenic seizures (AGS) are located primarily in the brainstem. Previous studies suggested a role for the periaqueductal grey (PAG) in the AGS network. The present study evaluated this possibility in genetically-epilepsy prone rats (GEPR-9s) by examining the effects of bilateral focal microinjection of a competitive NMDA receptor antagonist (DL-2-amino-7-phosphonoheptanoic acid (AP7), 1 and 5 nmol/side), a GABA(A) agonist (gaboxedol (THIP), 10 and 15 nmol) or an opioid peptide receptor antagonist (naloxone, 5 nmol) into PAG, based on the proposed role of these receptors in PAG neurotransmission. Blockade of NMDA receptors by AP7 (both doses) or activation of GABA(A) receptors with THIP (15 nmol/side) in the PAG suppressed AGS susceptibility. Naloxone displayed a seizure-suppressant effect that was delayed and incomplete. The seizure suppressant effect of AP7 or naloxone, unlike THIP, was observed at doses that did not produce motor quiescence. These data suggest that the PAG is a requisite nucleus in the neuronal network for AGS in GEPR-9s and that GABA(A), opioid peptide and NMDA receptors in the PAG modulate AGS propagation.

Topics: 2-Amino-5-phosphonovalerate; Animals; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA-A Receptor Agonists; Isoxazoles; Male; Microinjections; Naloxone; Narcotic Antagonists; Nerve Net; Periaqueductal Gray; Rats; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Seizures

The possible development of acute and chronic tolerance to 4, 5, 6, 7-tetrahydroisoxazole-(5, 4-C)pyridin-3-ol (THIP) and muscimol-induced analgesia was tested using the acetic acid induced writhing assay. Acute tolerance developed to their analgesic actions on repeated exposure at a 4-h interval which was sensitive to naloxone. Chronic tolerance gradually developed to these agents from the 4th day and was appreciable after 10 days of treatment. Injection of THIP or muscimol prior to morphine attenuated the acute tolerance developed to morphine analgesia. These findings reveal that acute and chronic tolerance developed to THIP and muscimol induced analgesia and are suggestive of a role for opioidergic system in the development of acute tolerance to their analgesic effect. However, these agents per se did not produce any dependence phenomena and failed to affect morphine dependence indicating that different mechanisms might be operating in the development of tolerance and dependence.

Topics: Analgesics; Animals; Drug Interactions; Drug Tolerance; Isoxazoles; Male; Mice; Morphine; Muscimol; Naloxone; Substance-Related Disorders

Immunohistochemical analysis documented the presence of gamma-aminobutyric acid (GABA)-containing fibers and GABA-containing chromaffin cells in canine adrenal glands. A dense network of fibers was visualized at the boundary between medullary and cortical cells, and, in the medullary tissue, GABA-containing fibers surrounded chromaffin cells. Some of these fibers enter the adrenal medulla together with splanchnic cholinergic nerves. The functional role of the GABAergic system in the regulation of catecholamine release from adrenal chromaffin cells was studied in canine adrenal glands in situ, using an autoperfusion system for the adrenal gland that was designed to eliminate indirect central effects of drugs or their metabolites on catecholamine release. The present study documents that GABA modulates the spontaneous release of catecholamines and the release elicited by electrical stimulation of the splanchnic nerve. GABAA receptor agonists such as THIP or muscimol increased the catecholamine content in adrenal effluent blood, whereas bicuculline (0.05 mmol/2 ml min-1), a GABAA receptor antagonist, reduced it. Baclofen (0.094 mmol/2 ml min-1), a GABAB receptor agonist, failed to alter the catecholamine content in adrenal effluent blood. The increased release of catecholamines elicited by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3[2H]-one (THIP; 0.143 mmol/2 ml min-1) was prevented by bicuculline (0.05 mmol/2 ml min-1) but not by hexamethonium (2.48 mmol/2 ml min-1) or naloxone (0.122 mmol/2 ml min-1). Furthermore, denervation of the adrenal glands failed to prevent the THIP-elicited release of catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Medulla; Animals; Baclofen; Bicuculline; Chromaffin Granules; Dogs; Electric Stimulation; Epinephrine; Female; Hexamethonium; Hexamethonium Compounds; Histocytochemistry; Isoxazoles; Muscimol; Naloxone; Norepinephrine; Receptors, GABA-A; Splanchnic Nerves

The antinociceptive actions of intraperitoneally-administered 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and morphine were compared using three strains of mice. With the hot-plate assay, ED50 values for the action of THIP were about 4 mg/kg in OF1, CD1 and NMRI strains, whereas ED50 values for morphine varied among strains, being 6.8 mg/kg for OF1, 16.9 mg/kg for CD1, and about 29 mg/kg for NMRI mice; thus, the genetic control of the analgesic action of THIP appears to differ from that of morphine. The analgesic action of THIP in the hot-plate test was not blocked by naloxone, bicuculline, phentolamine or methysergide, but was partially reversed by a high dose of atropine, indicating that classic opiate-receptors, bicuculline-sensitive GABA-receptors, alpha-adrenoceptors and serotonin-receptors do not appear to mediate the action of THIP but that cholinergic receptors might be indirectly involved. THIP was about equipotent or more potent than morphine in the phenylbenzoquinone writhing test, evasion test, and traction test. Since the ED50 values for THIP in OF1 mice were similar for hot-plate, evasion and traction tests, the analgesic action of THIP might not be readily dissociated from its sedative or myorelaxant action.

Topics: Analgesics; Animals; Atropine; Benzoquinones; Bicuculline; Hypnotics and Sedatives; Isoxazoles; Male; Mice; Morphine; Naloxone; Oxazoles; Quinones; Reaction Time