European journal of pharmacology
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The periaqueductal gray (PAG) is a major component of the descending pain inhibitory pathway, which is related to central analgesia. In the present study, we have investigated the possible roles of presynaptic nicotinic acetylcholine receptors in GABAergic transmission onto PAG neurons. In acutely isolated rat PAG neurons, GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded by use of a whole-cell patch clamp technique. ⋯ The nicotine-induced increase in mIPSC frequency was completely occluded in the presence of Cd2+, a general voltage-dependent Ca2+ channels blocker, and in the absence of extracellular Ca2+ or Na+. The results suggest that presynaptic nicotinic receptors are less permeable to Ca2+, and that the activation of these receptors depolarizes GABAergic nerve terminals. In conclusion, presynaptic nicotinic receptors would temporally regulate the excitability of PAG neurons being not overexcited and eventually contribute to the cholinergic modulation of output from the PAG.
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We recently identified 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), the first allosteric metabotropic glutamate (mGlu) 7 receptor-selective negative allosteric modulator. In this study, we examined the in vivo pharmacological effects of MMPIP on the central nervous system. MMPIP was distributed into the brain after systemic administration in both mice and rats. ⋯ No analgesic effects of MMPIP were detected in either the tail immersion test or formalin test in mice. MMPIP did not alter the threshold for induction of seizures by electrical shock or pentylenetetrazole in mice. These findings suggest that blockade of mGlu(7) receptors by MMPIP may modulate both non-spatial and spatial cognitive functions without non-selective inhibitory effects on the central nervous system.