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Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund's adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. Intrathecal pretreatment or post-treatment of a 5-HT3 receptor antagonist (Y-25130 or ondansetron) blocked the SP-induced hyperalgesia. The SP-induced hyperalgesia was both GABA A and NMDA receptor-dependent after pre-and post-treatment with selective antagonists at the spinal level. A microinjection of SP into the RVM also led to increased NMDA NR1 receptor subunit phosphorylation in spinal cord tissue. The GABA A receptormediated hyperalgesia involved a shift in the anionic gradient in dorsal horn nociceptive neurons and an increase in phosphorylated NKCC1 protein (isoform of the Na-K-Cl cotransporter). Following a low dose of SP infused into the RVM, intrathecal muscimol (GABA A agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABA A receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABA A and NMDA receptors.Keywords substance P; inflammation; brainstem; serotonin; NMDA receptor; GABA A receptor Brainstem descending pathways constitute a major mechanism in pain modulation. Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM) Porreca et al., 2002;Vanegas and Schaible, 2004). These circuits include facilitatory and inhibitory mechanisms. Little is known about the chemical mediators that NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 June 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript contribute to initiation and maintenance of descending facilitation and their role in inflammation-induced hyperalgesia.We have now confirmed our earlier preliminary report (LaGraize et al., 2005) that substance P (SP) and its neurokinin-1 (NK-1) tachykinin receptor in the RVM participate in mechanisms of descending facilitation and behavioral hyperalgesia. Our results are consistent with recent studies showing that SP microinjected into the RVM induces hyperalgesia in non-inflamed animals and NK-1R antagonists in the RVM attenuate inflammation-induced hyperalgesia (Budai et al., 2007;Pacharinsak et al., 2008;Hamity et al., 2010). The hyperalge...

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Key points• Low-frequency (4-14 Hz, 'theta') neuronal oscillations are essential for various animal behaviours, and are strongly influenced by inhibitory neuronal activity, although the interneurons responsible for such activity are not known.• We used optogenetic methods to identify the generators of cholinergically activated, theta-frequency inhibitory postsynaptic currents (IPSCs) in mouse CA1 hippocampus.• Rhythmic IPSCs are driven by the activation of muscarinic acetylcholine receptors (mAChRs) via mAChR agonist application or ACh release from cholinergic axons.• The output of parvalbumin (PV)-expressing interneurons was prevented optogenetically or pharmacologically without affecting mAChR-dependent oscillatory IPSCs. Instead, these IPSCs were blocked by inhibiting interneurons that express glutamic acid decarboxylase 2 (Gad2) and cannabinoid receptors, primarily the cholecystokinin (CCK)-expressing cells.• Theta-frequency IPSCs were also inhibited by a μ-opioid receptor agonist, suggesting that, in addition to being a potential substrate for the generation of behaviourally important rhythms, the same interneurons are a site of convergence of the cannabinoid and opioid neuromodulatory systems.Abstract Neuronal electrical oscillations in the theta (4-14 Hz) and gamma (30-80 Hz) ranges are necessary for the performance of certain animal behaviours and cognitive processes. Perisomatic GABAergic inhibition is prominently involved in cortical oscillations driven by ACh release from septal cholinergic afferents. In neocortex and hippocampal CA3 regions, parvalbumin (PV)-expressing basket cells, activated by ACh and glutamatergic agonists, largely mediate oscillations. However, in CA1 hippocampus in vitro, cholinergic agonists or the optogenetic release of endogenous ACh from septal afferents induces rhythmic, theta-frequency inhibitory postsynaptic currents (IPSCs) in pyramidal cells, even with glutamatergic transmission blocked. The IPSCs are regulated by exogenous and endogenous cannabinoids, suggesting that they arise from type 1 cannabinoid receptor-expressing (CB1R+) interneurons -mainly cholecystokinin (CCK)-expressing cells. Nevertheless, an occult contribution of PV-expressing interneurons to these rhythms remained conceivable. Here, we directly test this hypothesis by selectively silencing CA1 PV-expressing cells optogenetically with halorhodopsin or archaerhodopsin. However, this had no effect on theta-frequency IPSC rhythms induced by carbachol (CCh). In contrast, the silencing of glutamic acid decarboxylase 2-positive interneurons, which include the CCK-expressing basket cells, strongly suppressed inhibitory oscillations; PV-expressing interneurons appear to play no role. The low-frequency IPSC oscillations induced by CCh or optogenetically stimulated ACh release were also inhibited by a μ-opioid receptor ( which was unexpected because MORs in CA1 are not usually associated with CCK-expressing cells. Our results reveal novel properties of an inhibitory oscillator circuit within CA1 that is activated ...

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