The Histamine H(4) Receptor Participates in the Anti-Neuropathic Effect of the Adenosine A(3) Receptor Agonist IB-MECA: Role of CD4(+) T Cells

A(3) adenosine receptor (A(3)AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H(4) histamine receptor (H(4)R), 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 A(3)AR and H(4)R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A(3)AR agonist IB-MECA (0.5 mg/kg) and the H(4)R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H(4)R(−/−) 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 H(4)R(−/−) 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 A(3)AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4(+) T cells throughout IL-10 up-regulation.