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

Abstract

Histamine plays a complex role in pain modulation with opposite roles in nociception for histamine receptor subtypes 1, 2, and 3. The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses with a proinflammatory activity, but little is known about the 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 model of neuropathic pain. ST-1006 counteracted mechanical allodynia in neuropathic mice, an effect prevented by the H4R antagonist JNJ 10191584. In spared nerve injury mice, an early over-phosphorylation of ERK1 and ERK2 was observed in the dorsal root ganglia (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 3 MAPK within DRG, and phosphorylation of ERK1, ERK2, and 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 after 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.

Aryl-1,3,5-triazine ligands of histamine H4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

“…In contrast, recently published papers revealed that H 4 R stimulation exhibited pain-reducing effects [38–40]. Taken together, all these data suggest that H 4 R antagonists might possess anti-hyperalgesic properties that are secondary to decreased release of inflammatory mediators, whereas activation of neuronal H 4 Rs, especially those localized on sensory dorsal root ganglion neurons, might result in antinociceptive effects in the absence of inflammation [39]. …”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…Sanna et al [119] studied the effects of agonism of neuronal H4 receptors in pain transmission. They found that activation of H4 receptors, primarily in the dorsal root ganglia, resulted in altered MAP kinase signaling and ultimately decreased pain transmission [119].…”

“…They found that activation of H4 receptors, primarily in the dorsal root ganglia, resulted in altered MAP kinase signaling and ultimately decreased pain transmission [119]. H4 receptor agonists are currently an active area of research, with some compounds being studied in clinical trials [120].…”

Inflammatory mediators of neuropathic pain

“…Effects on H4 receptors block in NP models are also still not clear. A study has shown that treatment with H4 agonists blocks mechanical sensitivity, while others have shown that systemic use of H4 antagonists has dose-dependent and reversible effect on mechanical hypersensitivity 33 . Histamine effect on NP is clearly shown, however further studies are needed before considering the use of selective histamine agonists/antagonists to manage NP 6 .…”

“…Peripheral and spinal activation of H3 receptors inhibits formalin-induced nociception 32 . Systemic administration of H3 receptors antagonists decreases mechanical sensitivity in experimental NP models 33 . In spite of the poor knowledge on the antinociception mechanism of anti-H3, they are already being clinically tested.…”