Intrathecal administration of low-dose nociceptin/orphanin FQ induces allodynia via c-Jun N-terminal kinase and monocyte chemoattractant protein-1.

Abstract

Pathological chronic pain, which is frequently associated with prolonged tissue damage, inflammation, tumour invasion, and neurodegenerative diseases, gives rise to hyperalgesia and allodynia. We previously reported that intrathecal administration of nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for the orphan opioid receptor-like receptor, in the femtomole range induces touch-evoked allodynia. N/OFQ has been implicated in multiple signalling pathways, such as inhibition of cAMP production and Ca(2+) channels, or activation of K(+) channels and mitogen-activated protein kinase, although the signalling pathways of N/OFQ-induced allodynia remain unclear. To address these issues, we developed an ex vivo mitogen-activated protein kinase assay by using intact slices of mouse spinal cord. N/OFQ markedly increased the phosphorylation of c-Jun N-terminal kinase (JNK) in the superficial dorsal horn of the spinal cord. The N/OFQ-stimulated JNK phosphorylation was significantly inhibited by pertussis toxin, the phospholipase C inhibitor U73122, and the inositol trisphosphate receptor antagonist Xestospongin C. Intrathecal administration of the JNK inhibitor SP600125 inhibited N/OFQ-evoked allodynia. The N/OFQ-induced increase in JNK phosphorylation was observed in astrocytes that expressed glial fibrillary acidic protein. N/OFQ also induced monocyte chemoattractant protein-1 (MCP-1) release via the JNK pathway, and N/OFQ-induced JNK phosphorylation was observed in MCP-1-immunoreactive astrocytes. Intrathecal administration of the MCP-1 receptor antagonist RS504393 inhibited N/OFQ-evoked allodynia. These results suggest that, in the spinal dorsal horn, N/OFQ induces allodynia through activation of JNK via the phospholipase C-inositol trisphosphate pathway, which is coupled to pertussis toxin-sensitive G-protein, and following the release of MCP-1 from astrocytes.

• Authors: Kenta Kawabata, Isamu Nishimura, Takeshi Fujiwara, Shoko Terauchi, Toshiaki Minami, Seiji Ito, Emiko Okuda-Ashitaka
• Journal: The European journal of neuroscience (Eur J Neurosci) Vol. 43 Issue 11 Pg. 1499-508 (06 2016) ISSN: 1460-9568 [Electronic] France
• PMID: 27038234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chemical References

• Chemokine CCL2
• Opioid Peptides
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Astrocytes (metabolism)
• Chemokine CCL2 (metabolism)
• Hyperalgesia (chemically induced, metabolism)
• Injections, Spinal
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Opioid Peptides (administration & dosage)
• Phosphorylation
• Signal Transduction
• Spinal Cord (metabolism)
• Nociceptin