Role of cortical TRPV1 in resting and chronic pain conditions

Neuropathic pain (NP) is an idiopathic pathological condition characterized by a combination of different components: sensorial, cognitive and emotional-affective. Anterior cingulate cortex (ACC) is one of the brain areas involved in the emotional and motivational pain aspects. In NP this area undergoes peculiar changes such as increase of synaptic strength, structural reorganization and neurochemical alterations. On top of these, a substantial re-modeling of the endocannabinoid receptors at both peripheral and central level has been outlined. Among these receptors, activation and desensitization of TRPV1 promotes pro and anti-nociceptive responses, respectively. In the present study we observed that TRPV1 is mainly expressed in the microglia of ACC of mouse. Its activation, besides increasing spontaneous excitatory synaptic currents (mEPSCs) onto layer 2/3 pyramidal neurons also promotes a microglia inflammatory phenotype and induces microglia microvescicles (MVs) release . TRPV1 stimulation mediates microglia to neuron communication by promoting MVs shedding, which in turn enhances sphingosine metabolism on pre-synaptic terminals and increases neurotransmitter release probability. Conversely, we found that in the ACC of neuropathic pain mice,TRPV1 channels undergo a particular redistribution, appearing not only on microglial cells but even on neurons and directly participate to circuitry excitability. These data unveil that TRPV1 receptor is a microglial activity regulator during physiological conditions and an important synaptic player in chronic pain model.