Peripheral Purinergic Modulation in Pediatric Orofacial Inflammatory Pain Affects Brainstem Nitroxidergic System: A Translational Research.

Elisa Borsani,Rita Rezzani,Salvatore Scacco,Lorenzo Lo Muzio,Luigi Fabrizio Rodella,Barbara Buffoli,Michele Di Cosola,Riccardo Nocini,Mariarosaria Boccellino,Marina Di Domenico,Stefania Cantore,Andrea Ballini,Vittorio Dibello,Iole Vozza

doi:10.1155/2022/1326885

Abstract

Physiology of orofacial pain pathways embraces primary afferent neurons, pathologic changes in the trigeminal ganglion, brainstem nociceptive neurons, and higher brain function regulating orofacial nociception. The goal of this study was to investigate the nitroxidergic system alteration at brainstem level (spinal trigeminal nucleus), and the role of peripheral P2 purinergic receptors in an experimental mouse model of pediatric inflammatory orofacial pain, to increase knowledge and supply information concerning orofacial pain in children and adolescents, like pediatric dentists and pathologists, as well as oro-maxillo-facial surgeons, may be asked to participate in the treatment of these patients. The experimental animals were treated subcutaneously in the perioral region with pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS), a P2 receptor antagonist, 30 minutes before formalin injection. The pain-related behavior and the nitroxidergic system alterations in the spinal trigeminal nucleus using immunohistochemistry and western blotting analysis have been evaluated. The local administration of PPADS decreased the face-rubbing activity and the expression of both neuronal and inducible nitric oxide (NO) synthase isoforms in the spinal trigeminal nucleus. These results underline a relationship between orofacial inflammatory pain and nitroxidergic system in the spinal trigeminal nucleus and suggest a role of peripheral P2 receptors in trigeminal pain transmission influencing NO production at central level. In this way, orofacial pain physiology should be elucidated and applied to clinical practice in the future.

Highlights

Orofacial inflammatory pain is a universal healthcare complaint in pediatric patients and a major concern of national public health [1]
The local administration of PPADS decreased the face-rubbing activity and the expression of both neuronal and inducible nitric oxide (NO) synthase isoforms in the spinal trigeminal nucleus. These results underline a relationship between orofacial inflammatory pain and nitroxidergic system in the spinal trigeminal nucleus and suggest a role of peripheral P2 receptors in trigeminal pain transmission influencing NO production at central level
The results of this study suggest the correlation between the nitroxidergic system in the brainstem and peripheral P2 receptor modulation in orofacial inflammatory pain transmission contributing to the insight of this pathology [36]

Summary

Introduction

Orofacial inflammatory pain is a universal healthcare complaint in pediatric patients and a major concern of national public health [1]. ATP can act as an extracellular signalling molecule [7, 8], influencing various biological functions, and stimulating nociceptors to initiate pain sensation by inducing the synthesis and release of proinflammatory cytokines and nitric oxide (NO) [9, 10]. Some studies have suggested that NOS/NO may play a role in pathological pain states [13, 14]. In this regard, nNOS activity appears to influence pain transmission [10] while iNOS is expressed only in pathological conditions and is induced by proinflammatory cytokines and/or endotoxins [15]. Lee and coworkers [22] observed a timedependent increase in nNOS and iNOS protein expression in the spinal trigeminal nucleus following capsaicin injection in the masseter muscle and a significant attenuation of hypersensitivity after the pretreatment with NOS inhibitors in rats

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