RESUMO
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2-/-) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2-/- mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.
Assuntos
Gânglios Espinais/fisiopatologia , Imunoglobulina G/administração & dosagem , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Dor Nociceptiva/imunologia , Dor Nociceptiva/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Células Cultivadas , Feminino , Humanos , Imunização Passiva , Masculino , Mecanotransdução Celular , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Células do Corno Posterior/fisiologia , Superfamília Shaker de Canais de Potássio/fisiologiaRESUMO
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.