CB 1 -cannabinoid-, TRPV 1 -vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms.

Neuropathic pain (NP) is a challenge due to our limited understanding of the mechanisms that initiate and maintain chronic pain. The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is an important area of the emotional and cognitive components of pain and pharmacological systems can interact into the neocortex to elaborate the chronic pain. This work aimed to investigate the pharmacological cross-talk between synaptic neurotransmission, neuroanatomical approaches and NP conditions. A bidirectional neuron tracer, the 3000-molecular-weight biodextran (BDA) was microinjected into the PrL cortex. The mechanical withdrawal threshold (MWT) was recorded by a von Frey test, and the effect of prelimbic cortex CB1 , NMDA, and TRPV1 receptor modulation was evaluated 21 days after chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. Microinjection of a bidirectional neurotracer in the PrL cortex showed connections with the lateral division of the mediodorsal thalamic nucleus (MDL), central division of the mediodorsal thalamic nucleus (MDC), centrolateral thalamic nucleus (CL), ventromedial thalamic nucleus (VM), and in the paracentral thalamic nucleus (PC). In detail, AM251, a CB1 antagonist receptor, (at 50, 100 and 200 pmol) intra-PrL cortex microinjections decreased the MWT. Administration of 6-iodonordihydrocapsaicin (6-I-CPS), a transient receptor potential vanilloid type 1 (TRPV1 ) antagonists, at 3 nmol and endocannabinoid anandamide (AEA) at 50 and 100 pmol increased the MWT. AEA at 200 pmol injected in the PrL cortex decreased the MWT, and this hyperalgesic effect was blocked by 6-I-CPS at 3 nmol. The AEA (at 100 pmol) anti-allodynic effect was attenuated by AM251 (at 5 pmol). The TRPV1 selective agonist N-oleoyldopamine (OLDA) at 10 µM decreased the MWT. The blockade of the NMDA receptor with LY235959 (at 8 nmol) and 6-I-CPS (at 3 nmol) reversed the OLDA (at 10 µM) hyperalgesic effect. These findings showed that the PrL cortex sends pathways to the thalamic nucleus that can mediate the nociception ´s transmission. We also suggest that the PrL cortex is involved in the potentiation and maintenance of mechanical allodynia by NMDA and TRPV1 receptor activation and that attenuation of this allodynia depends on CB1 receptor activation during NP.