A possible neural mechanism for photosensitivity in chronic pain.

Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but it cannot be attributed to a general increase in cortical sensory processing. Here, we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of pain-modulating systems in the brain. These individuals expressed discomfort at light levels substantially lower than that of healthy control subjects. Complementary studies in lightly anesthetized rat demonstrated that a subset of identified pain-modulating neurons in the rostral ventromedial medulla unexpectedly responds to light. Approximately half of the pain-facilitating "ON-cells" and pain-inhibiting "OFF-cells" sampled exhibited a change in firing with light exposure, shifting the system to a pronociceptive state with the activation of ON-cells and suppression of OFF-cell firing. The change in neuronal firing did not require a trigeminal or posterior thalamic relay, but it was blocked by the inactivation of the olivary pretectal nucleus. Light exposure also resulted in a measurable but modest decrease in the threshold for heat-evoked paw withdrawal, as would be expected with engagement of this pain-modulating circuitry. These data demonstrate integration of information about light intensity with somatic input at the level of single pain-modulating neurons in the brain stem of the rat under basal conditions. Taken together, our findings in rodents and humans provide a novel mechanism for abnormal photosensitivity and suggest that light has the potential to engage pain-modulating systems such that normally innocuous inputs are perceived as aversive or even painful.

Striatal cholinergic interneurons Drive GABA release from dopamine terminals.

Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.

Control of basal ganglia output by direct and indirect pathway projection neurons.

The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.

Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling.

BACKGROUND: Mice lacking type 1 equilibrative nucleoside transporter (ENT1(-/-)) exhibit increased ethanol-preferring behavior compared with wild-type littermates. This phenotype of ENT1(-/-) mice appears to be correlated with increased glutamate levels in the nucleus accumbens (NAc). However, little is known about the downstream consequences of increased glutamate signaling in the NAc. METHODS: To investigate the significance of the deletion of ENT1 and its effect on glutamate signaling in the NAc, we employed microdialysis and iTRAQ proteomics. We validated altered proteins using Western blot analysis. We then examined the pharmacological effects of the inhibition of the N-methyl-D-aspartate (NMDA) glutamate receptor and protein kinase Cγ (PKCγ) on alcohol drinking in wild-type mice. In addition, we investigated in vivo cyclic adenosine monophosphate response element binding activity using cyclic adenosine monophosphate response element-ß-galactosidase mice in an ENT1(-/-) background. RESULTS: We identified that NMDA glutamate receptor-mediated downregulation of intracellular PKCγ-neurogranin-calcium-calmodulin dependent protein kinase type II signaling is correlated with reduced cyclic adenosine monophosphate response element binding activity in ENT1(-/-) mice. Inhibition of PKCγ promotes ethanol drinking in wild-type mice to levels similar to those of ENT1(-/-) mice. In contrast, an NMDA glutamate receptor antagonist reduces ethanol drinking of ENT1(-/-) mice. CONCLUSIONS: These findings demonstrate that the genetic deletion or pharmacological inhibition of ENT1 regulates NMDA glutamate receptor-mediated signaling in the NAc, which provides a molecular basis that underlies the ethanol-preferring behavior of ENT1(-/-) mice.