The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Jul 1999
Ethanol directly depresses AMPA and NMDA glutamate currents in spinal cord motor neurons independent of actions on GABAA or glycine receptors.
Ethanol is a general anesthetic agent as defined by abolition of movement in response to noxious stimulation. This anesthetic endpoint is due to spinal anesthetic actions. This study was designed to test the hypothesis that ethanol acts directly on motor neurons to inhibit excitatory synaptic transmission at glutamate receptors. ⋯ The results show that ethanol exerts direct depressant effects on both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate currents in motor neurons. Enhancement of gamma-aminobutyric acidA and glycine inhibition is not required for this effect. Direct depression of glutamatergic excitatory transmission by a postsynaptic action on motor neurons thus may contribute to general anesthesia as defined by immobility in response to a noxious stimulus.
-
J. Pharmacol. Exp. Ther. · Jul 1999
Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist.
In addition to its central actions, morphine has important peripheral effects. To examine peripheral analgesic mechanisms, we developed a topical opioid paradigm in which the tail was immersed in a dimethyl sulfoxide (DMSO) solution containing various drugs. Alone, DMSO was inactive in the tail-flick assay in mice. ⋯ The ability of a topical NMDA antagonist to block local morphine tolerance suggests that peripheral NMDA receptors mediate topical morphine tolerance. Morphine was cross-tolerant to DAMGO, but not to morphine-6beta-glucuronide, implying different mechanisms of action. These observations are significant in the design and use of opioids clinically.
-
J. Pharmacol. Exp. Ther. · Jul 1999
Expression of multiple alpha1-adrenoceptors on vascular smooth muscle: correlation with the regulation of contraction.
Previous work has shown that the genes encoding each alpha1-adrenoceptor subtype are coexpressed throughout the peripheral vascular system. We have evaluated subtype-selective antibodies as tools to determine the extent of protein expression in arteries. The alpha1A-, alpha1B-, and alpha1D-adrenoceptors were detected in the medial layer of the aorta, caudal, femoral, iliac, renal, superior mesenteric, and mesenteric resistance arteries. ⋯ The expression of each alpha1-adrenoceptor was significantly decreased by in vivo application of antisense oligonucleotides targeted against each subtype. Inhibition of the expression of only one, the alpha1A in renal and the alpha1D in femoral arteries, reduced the contractile response to naphazoline. The results show: 1) subtype-selective antibodies can be used in tissues and cell culture to localize the alpha1-adrenoceptor subtypes, 2) in addition to expression on the cell surface, the alpha1-adrenoceptors are expressed intracellularly, and 3) despite expression of all adrenoceptors, a single subtype mediates the contractile response in the femoral and renal arteries.
-
J. Pharmacol. Exp. Ther. · Jul 1999
Moxonidine, a selective alpha2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice.
alpha2-Adrenergic receptor (AR)-selective compounds produce antihypertensive and antinociceptive effects. Moxonidine alleviates hypertension in multiple species, including humans. This study demonstrates that intrathecally administered moxonidine produces antinociception in mice. ⋯ Conversely, absence of clonidine efficacy in D79N-alpha2a mice implies that alpha2aAR activation enables clonidine-induced antinociception. When clinically administered, moxonidine induces fewer side effects relative to clonidine; moxonidine-induced antinociception appears to involve a different alpha2AR subtype than clonidine-induced antinociception. Therefore, moxonidine may prove to be an effective treatment for pain with an improved side effect profile.
-
J. Pharmacol. Exp. Ther. · Jul 1999
Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A.
Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. ⋯ These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.