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G-protein coupled receptor H4 (H4R) is a histamine receptor subtype that is involved in a condition of pathological chronic pain, but its pathophysiological function is unknown. Here, we investigate the role of H4R in a model of traumatic nerve injury. H4R knockout (H4R−/−) mice exposed to spared nerve injury (SNI) developed a more prominent mechanical and thermal hypersensitivity than wild type mice. Western blotting and immunofluorescence were used to characterize the cellular mechanisms. Nerve injury increased phosphorylated pERK MAPK expression in the spinal cord that was further promoted in H4R−/− genotype. Additionally, the increase in the phosphorylated cAMP response element-binding protein (CREB) was significantly enhanced in neuropathic H4R−/− mice. In the same way, after SNI a remarkable increase of dopamine beta-hydroxylase (DβH) immunoreactive neurons was detected in spinal cord of H4R−/− mice. The number of injured DRG neurons after SNI of H4R−/− mice, identified by activating transcription factor 3 (ATF3) staining was comparable to that of wild type littermates. Similarly the density of intraepidermal nerve fibres in plantar skin after SNI was reduced with the same degree in H4R−/− mice and with wild type mice. We conclude that the phenotype of H4R−/− mice leads to increased neuropathic pain hypersensitivity promoting an overactivation of spinal ERK-CREB pathway in DβH expressing neurons without modifying the innervation of the hind paw skin and integrity of the primary sensory neurons. In summary, our results provide H4R as a potential new target for the clinical management of chronic neuropathic pain conditions.Role of H4R in nociceptive signaling.Characterization of signaling pathway responsible of hypernociceptive phenotype in H4R−/− mice.Modulation of ERK pathway in DβH expressing neurons.