Growing evidence regarding the function of vanilloid receptor-1 (VR1) in the brain suggests potential central roles of this receptor, previously described to occur primarily in peripheral sensory neurons. In the present study, we used electrophysiological and biochemical techniques to investigate the function and the endogenous stimulation of VR1 in dopaminergic neurons of the substantia nigra pars compacta (SNc). The VR1 agonist capsaicin increased the frequency of both TTX-sensitive and -insensitive spontaneous EPSCs (sEPSCs) without affecting their amplitude, suggesting a presynaptic site of action. In contrast, no effect was detected with regard to GABAergic transmission. No increase in sEPSC frequency was observed in the presence of cadmium chloride, while the voltage-dependent calcium channel antagonist omega-conotoxin MVIIC did not prevent capsaicin action. The VR1 antagonists capsazepine and iodoresiniferatoxin (IRTX) blocked the effects of capsaicin. Importantly, IRTX per se reduced sEPSC frequency, suggesting a tonic activity of VR1. The endogenous VR1 agonist anandamide (AEA) produced an IRTX-sensitive increase in the frequency of sEPSCs on dopaminergic neurons that was more pronounced when protein kinase A had been activated. Furthermore, mass spectrometric analyses and binding experiments revealed high levels of endogenous AEA and specific binding of AEA to VR1 receptors in the SNc. These data suggest a tonic facilitation of glutamate release exerted by VR1 in the SNc through a stimulation of VR1 by endovanilloids, including anandamide. The increase in sEPSC frequency by VR1 onto midbrain dopaminergic neurons suggests the involvement of these receptors in motor and cognitive functions involving the dopaminergic system.

The capsaicin receptor TRPV1 has been widely characterized in the sensory system as a key component of pain and inflammation. A large amount of evidence shows that TRPV1 is also functional in the brain although its role is still debated. Here we report that TRPV1 is highly expressed in microglial cells rather than neurons of the anterior cingulate cortex and other brain areas. We found that stimulation of microglial TRPV1 controls cortical microglia activation per se and indirectly enhances glutamatergic transmission in neurons by promoting extracellular microglial microvesicles shedding. Conversely, in the cortex of mice suffering from neuropathic pain, TRPV1 is also present in neurons affecting their intrinsic electrical properties and synaptic strength. Altogether, these findings identify brain TRPV1 as potential detector of harmful stimuli and a key player of microglia to neuron communication.

The vanilloid receptor protein (VR1) is a well‐characterised integrator of noxious stimuli in peripheral sensory neurones. There is evidence for the presence of VR1 in the central nervous system, but little information as to its role there. In this study we have examined the actions of agonists for VR1 receptors in the rat locus coeruleus (LC), using whole‐cell patch‐clamp recordings from acutely isolated neurones and neurones in slices. Superfusion with capsaicin resulted in a concentration‐dependent increase in the frequency of isolated miniature excitatory postsynaptic currents (mEPSCs) in LC neurones. The mean amplitude of the mEPSCs was not affected by capsaicin. The effects of capsaicin (1 μM) were abolished by the VR1 receptor antagonists capsazepine (10 μM) and iodoresiniferatoxin (300 nm). Removal of extracellular Ca2+ abolished the capsaicin‐induced increase in frequency of mEPSCs. Capsaicin superfusion had no consistent effects on evoked excitatory postsynaptic currents. Capsaicin superfusion also resulted in the release of an adrenoceptor agonist in the LC but did not affect the membrane currents of acutely isolated LC neurones. These data demonstrate that the VR1 receptor appears to be located presynaptically on afferents to the LC, and that activation of VR1 may serve to potentiate the release of glutamate and adrenaline/noradrenaline in this brain region.