The Histamine H<sub>4</sub> Receptor Participates in the Anti-Neuropathic Effect of the Adenosine A<sub>3</sub> Receptor Agonist IB-MECA: Role of CD4<sup>+</sup> T Cells
Laura Micheli,
Mariaconcetta Durante,
Elena Lucarini,
Silvia Sgambellone,
Laura Lucarini,
Lorenzo Di Cesare Mannelli,
Carla Ghelardini,
Emanuela Masini
Affiliations
Laura Micheli
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Mariaconcetta Durante
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Elena Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Silvia Sgambellone
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Laura Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Lorenzo Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Carla Ghelardini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
Emanuela Masini
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Florence, Italy
A3 adenosine receptor (A3AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H4 histamine receptor (H4R), also implicated in pain modulation, is expressed on T cells playing a preeminent role in its activation and release of IL-10. To improve the therapeutic opportunities, this study aimed to verify the hypothesis of a possible cross-talk between A3AR and H4R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A3AR agonist IB-MECA (0.5 mg/kg) and the H4R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H4R−/− mice, IB-MECA activity was reduced, lower pain relief and lower modulation of plasma IL-1β, TNF-α, IL-6 and IL-10 were shown. The complete anti-allodynia effect of IB-MECA in H4R−/− mice was restored after intravenous administration of CD4+ T cells obtained from naïve wild type mice. In conclusion, a role of the histaminergic system in the mechanism of A3AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4+ T cells throughout IL-10 up-regulation.
