Title

 

Authors

L. Gatta¹, S. Boccella¹, D. Vita¹, L. Luongo¹, G. Bellini¹, M. De Chiaro¹, I. Marabese¹, D. Siniscalco¹, F. Piscitelli², V. Di Marzo², E. Palazzo¹, F.sca Rossi³, S. Maione¹, V. de Novellis¹.

¹Department of Experimental Medicine, Pharmacology Division, The Second University of Naples
²Istituto di biochimica Consiglio Nazionale delle Ricerche, via dei Campi Flegrei 34, 80078, Pozzuoli (NA)
³Department of Pediatrics, Second University of Naples, Italy

 

Abstract

Neuropathic pain is a chronic disease resulting from dysfunction within the “pain matrix”. The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. Among the novel targets identified for chronic pain therapy, the transient receptor potential vanilloid subtype 1 (TRPV1) is attracting increasing interest, since it plays a central role in the transduction of pain. In this study, we have investigated the involvement of TRPV1 receptor and the fatty acid amide hydrolase (FAAH), the catabolic enzyme of endocannabinoids/endovanilloids, in the morphofunctional changes occurring in the pre-limbic/infra-limbic (PL/IL) cortex in neuropathic rats. We have investigated the effect of chronic treatment with N-arachidonoyl-serotonin (AA-5-HT), a unique compound with the “dual” ability to inhibit the FAAH, and antagonize TRPV1 receptors. The effect of AA-5-HT was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. We observed that BLA stimulation could evoke two distinct types of firing changes in separate populations of mPFC responding neuronsThe more commonly observed response was a robust inhibition of neural activity. Specifically, a cell was considered to be inhibited by BLA stimulation if it displayed a complete cessation of spontaneous firing after BLA stimulation. A second group of neurons displaying an increased of neural activity. This group of neurons showed a fast-onset burst of firing after BLA stimulation. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after chronic  treatment with AA-5-HT.The current study shows that SNI can shift the balance of excitatory and inhibitory responses in the BLA-mPFC pathway, resulting in a net increase in the excitatory influence that the BLA exerts over the PL/IL neuron population of the mPFC. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively.These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain.