Nitric oxide increases the spontaneous firing rate of rat medial vestibular nucleus neurons in vitro via a cyclic GMP‐mediated PKG‐independent mechanism

Abstract

The effects of nitric oxide (NO) on the discharge rate of medial vestibular nucleus neurons (MVNn) were investigated in rat brainstem slices. The NO-donor sodium nitroprusside (SNP, 200 microM) caused a marked enhancement (+36.7%) of MVNn spontaneous firing rate, which was prevented by the NO-scavenger, carboxy-PTIO (300 microM). The SNP effects were not modified (+37.4%) by synaptic uncoupling, suggesting that NO influences intrinsic membrane properties of MVNn rather than the synaptic input they receive. The excitatory action of SNP was virtually abolished by slice pretreatment with the soluble guanylyl cyclase inhibitor, ODQ (10 microM), and it was mimicked (+33.1%) by the cGMP analogue 8-Br-cGMP (400 microM). Protein kinase G (PKG) and cAMP/protein kinase A (PKA) were both excluded as downstream effectors of the NO/cGMP-induced excitation. However, the cyclic nucleotide-gated (CNG) channel blockers, L-cis-diltiazem (LCD, 100 microM) and Sp-8-Br-PET-cGMPS (100 microM), significantly reduced the firing rate increase produced by 8-Br-cGMP. Moreover, LCD alone decreased spontaneous MVNn firing (-19.7%), suggesting that putative CNG channels may contribute to the tonic control of resting MVNn discharge. 8-Br-cAMP (1 mM) also elicited excitatory effects in MVNn (+40.8%), which occluded those induced by 8-Br-cGMP, indicating that the two nucleotides share a common target. Finally, nested-polymerase chain reaction assay revealed the expression of CNG channel alpha subunit transcript in MVNn. Our data provide the first demonstration that NO/cGMP signalling modulates MVNn spontaneous firing through a mechanism that is independent of PKG or PKA and probably involves activation of CNG channels.

Inhibition of neuronal nitric oxide synthase prevents alterations in medial prefrontal cortex excitability induced by repeated cocaine administration

“…It has been reported that NO participates in numerous functions in the CNS (Bon and Garthwaite 2003;Garthwaite and Boulton 1995;Schuman and Madison 1994;Lin et al 2010;Vincent 2010;Garthwaite 2008), and its role in the regulation of neuronal excitability has been demonstrated (Centonze et al 2001;Podda et al 2004;Xu et al 1998). Indeed, NO actions in the CNS are frequently documented as modulation of ion channels (Ahern et al 2002;Grassi et al 2004).…”

Expression of cyclic nucleotide-gated channels in the rat medial vestibular nucleus

“…Nested PCR Nested-PCR assay was performed on MVN isolated from the brainstem of 8 rats, as previously described [11]. Primers sequences were: PCR (first round), forward, 5 0 -GAT ATT AAA CTA ACC ATG AAG AC-3 0 ; reverse, 5 0 -TAA CAG CCG GTT CAA CCT GAT-3 0 (product size 816 bp) [6]; nested PCR (second round), forward, 5 0 -AGG CAC CAT GGC TCT TTT CAA T-3 0 ; reverse, 5 0 -GAA CGT CAA GTT TAA ACT GCA G-3 0 (product size 500 bp).…”

“…Recent findings by our group suggest a role for CNG channels in the modulation of medial vestibular nucleus neuron (MVNn) excitability [11]. We demonstrated that nitric oxide (NO) increases the spontaneous firing rate of MVNn via cGMP-mediated, protein kinase-independent mechanism.…”

“…CNG channels are now recognized as an important target of cyclic nucleotides in the central nervous system (CNS). Electrophysiological and molecular data indicate that these channels, especially the olfactory-and rod-types, are widely distributed and functionally active in many regions of the brain, including the hippocampus, cerebral cortex, cerebellum, and brainstem [2,[4][5][6][7][8][9][10].Recent findings by our group suggest a role for CNG channels in the modulation of medial vestibular nucleus neuron (MVNn) excitability [11]. We demonstrated that nitric oxide (NO) increases the spontaneous firing rate of MVNn via cGMP-mediated, protein kinase-independent mechanism.…”

A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factorαand Interleukin-1βExpression

“…NO directly causes DRG neurons to lower their activation threshold, leading to increased hyperexcitability. Aberrant DRG activation and damage is thought to cause sensory neuronopathy, a diffuse and length-independent neuropathic pain syndrome (Zimmermann, 2001;Podda et al, 2004). Importantly, recent evidence indicates that proinflammatory cytokines, including TNFa and IL-1b, may participate in the resolution of tissue damage and recovery of nerve function (Austin and Moalem-Taylor, 2010;Nadeau et al, 2011).…”