British journal of pharmacology
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Recently, it was reported that anesthetizing infant rats for 6 h with a combination of anesthetic drugs (midazolam, nitrous oxide, isoflurane) caused widespread apoptotic neurodegeneration in the developing brain, followed by lifelong cognitive deficits. It has also been reported that ketamine triggers neuroapoptosis in the infant rat brain if administered repeatedly over a period of 9 h. The question arises whether less extreme exposure to anesthetic drugs can also trigger neuroapoptosis in the developing brain. ⋯ It was found that either ketamine or midazolam caused a dose-dependent, statistically significant increase in the rate of neuroapoptosis, and the two drugs combined caused a greater increase than either drug alone. The apoptotic nature of the neurodegenerative reaction was confirmed by electron microscopy. We conclude that relatively mild exposure to ketamine, midazolam or a combination of these drugs can trigger apoptotic neurodegeneration in the developing mouse brain.
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The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined mu-opioid receptor (MOP) regulation of voltage-gated calcium channel currents (I(Ca)) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice. Mice were injected s.c. with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). ⋯ Met-enkephalin-activated GIRK currents recorded in PAG slices were significantly smaller in neurons from CMT mice than vehicles, while GIRK currents activated by baclofen were unaltered. These data demonstrate that CMT-induced antinociceptive tolerance is accompanied by homologous reduction in the effectiveness of MOP agonists to inhibit I(Ca) and activate GIRK. Thus, a reduction in MOP number and/or functional coupling to G proteins accompanies the characteristic cellular adaptations to CMT previously described in PAG neurons.
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P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. ⋯ A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.
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Comparative Study
Amiloride protects against pentylenetetrazole-induced kindling in mice.
This study was performed to investigate whether or not amiloride, a sodium-hydrogen exchanger (NHE) inhibitor, can protect against seizure development of pentylenetetrazole (PTZ)-induced kindling in mice. Kindling was induced by once every 2 days treatment with PTZ (25 mg kg(-1) i.p.) for 5 weeks. Challenge experiments were carried out after 15 or 30 days of last treatment with PTZ. ⋯ The effect of amiloride on the incidence of PTZ-induced seizures was evident even after 15 or 30 days of last treatment. The results indicate a protective role for amiloride against PTZ-induced kindling in mice. The possibility of mediation of such effects by NHE inhibition is discussed.
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1. We investigated ethanol inhibition of the rat P2X(4) receptor and the contribution of the three histidine residues in the extracellular loop of this receptor to ethanol inhibition of receptor function, using site-directed mutagenesis and electrophysiological characterization of recombinant receptors. 2. In the wild-type receptor, 50, 200 and 500 mM ethanol increasingly shifted the ATP concentration-response curve to the right in a parallel manner, increasing the EC(50) value without affecting E(max). ⋯ In addition, ethanol decreased the desensitization rate of the H241A-mediated current. 5. The purinoceptor antagonists, suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), did not alter the magnitude of ethanol inhibition of ATP-activated current in the H241A mutant. 6. The results suggest that ethanol inhibits the wild-type rat P2X(4) receptor by an allosteric action to increase the EC(50) value of the ATP concentration-response curve, the P2X(4) receptor mutation H241A alters the mechanism by which ethanol inhibits P2X(4) receptor function, and ethanol and PPADS or suramin appear to inhibit H241A-mutated receptors at independent sites.