Growing evidence points to the histamine system as a promising target for the management of neuropathic pain. Preclinical studies reported the efficacy of HR antagonists in reducing pain hypersensitivity in models of neuropathic pain through an increase of histamine release within the CNS. Recently, a promising efficacy of HR agonists as anti-neuropathic agents has been postulated. Since HR and HR are both localized in neuronal areas devoted to pain processing, the aim of the study is to investigate the role of HR in the mechanism of anti-hyperalgesic action of the HR 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 HR antagonist JNJ 10191584 (6 µg/mouse i.t.; (10 µg/µL intraLC). Furthermore, GSK189254 was devoid of any anti-hyperalgesic effect in HR 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 HR to the HR antagonist-induced attenuation of hypernociceptive behavior in SNI mice. These results might help identify innovative therapeutic interventions for neuropathic pain.