The Histamine H 4 Receptor Participates in the Neuropathic Pain-Relieving Activity of the Histamine H 3 Receptor Antagonist GSK189254.

Growing evidence points to the histamine system as a promising target for the management of neuropathic pain. Preclinical studies reported the efficacy of H 3 R antagonists in reducing pain hypersensitivity in models of neuropathic pain through an increase of histamine release within the CNS. Recently, a promising efficacy of H 4 R agonists as anti-neuropathic agents has been postulated. Since H 3 R and H 4 R are both localized in neuronal areas devoted to pain processing, the aim of the study is to investigate the role of H 4 R in the mechanism of anti-hyperalgesic action of the H 3 R antagonist GSK189254 in the spared nerve injury (SNI) model in mice. Oral (6 mg/kg), intrathecal (6 µg/mouse), or intra locus coeruleus (LC) (10 µg/µL) administration of GSK189254 reversed mechanical and thermal allodynia in the ipsilateral side of SNI mice. This effect was completely prevented by pretreatment with the H 4 R antagonist JNJ 10191584 (6 µg/mouse i.t.; (10 µg/µL intraLC). Furthermore, GSK189254 was devoid of any anti-hyperalgesic effect in H 4 R deficient mice, compared with wild type mice. Conversely, pretreatment with JNJ 10191584 was not able to prevent the hypophagic activity of GSK189254. In conclusion, we demonstrated the selective contribution of H 4 R to the H 3 R antagonist-induced attenuation of hypernociceptive behavior in SNI mice. These results might help identify innovative therapeutic interventions for neuropathic pain.