Histamine H4 receptor activation alleviates neuropathic pain through differential regulation of ERK, JNK and P38 MAPK phosphorylation

Histamine plays a complex role in pain modulation with opposite roles in nociception for histamine receptor (HR) subtypes 1, 2 and 3. The H4R is expressed primarily on cells involved in inflammation and immune responses with a pro-inflammatory activity, but little is known aboutthe role in nociception of neuronal H4R. To investigate the effects of neuronal H4R in pain transmission, the effects produced by the H4R agonist ST-1006 were detected in the spared nerve injury (SNI) model of neuropathic pain. ST-1006 counteracted mechanical allodynia in neuropathic mice, an effect prevented by the H4R antagonist JNJ 10191584. In SNI mice an early over-phosphorylation of ERK1 and ERK2 was observed in the DRG, spinal cord and sciatic nerve. A progressive and long lasting activation of JNK1 was observed in the sciatic nerve and, to a lesser extent, in the spinal cord and DRG. An increased p-P38 content was detected in the spinal cord and DRG, with no modification in the sciatic nerve. Administration of ST-1006 prevented phosphorylation of all three MAPK within DRG, and phosphorylation of ERK1, ERK2, pJNK1 in the sciatic nerve. In the spinal cord the H4R agonist prevented selectively the pERK2 increase with no effect on pJNK1 and p-P38 levels. Double immunofluorescence experiments showed a neuronal localization and site of action for H4R. These findings suggest a prevalent modulation of ERK activity following H4R stimulation and indicate the DRG as prominent site of action for H4R-mediated antineuropathic activity. Targeting neuronal H4R with selective agonists could have therapeutic potential for neuropathic pain treatment.