The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury.
Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E(2), PGF(2alpha) or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride (JTC-801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ(-/-)) and the NOP receptor (NOP(-/-)). JTC-801 dose-dependently blocked the N/OFQ- and PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) induced allodynia in NOP(-/-) mice. By contrast, the N/OFQ-induced allodynia was not affected by inhibition of PG production by a 60-min pretreatment with the non-steroidal anti-inflammatory drug, indomethacin. Among PGE receptor (EP) subtype-selective agonists, the EP4 agonist, AE1-329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1-329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC-801. Conversely, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.
Okuda-Ashitaka
Emiko
E
Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi 570-8506, Japan.
Minami
Toshiaki
T
Matsumura
Shinji
S
Takeshima
Hiroshi
H
Reinscheid
Rainer K
RK
Civelli
Olivier
O
Ito
Seiji
S
D000634:Aminoquinolines / Q000008:administration & dosage; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001522:Behavior, Animal; D001549:Benzamides / Q000008:administration & dosage; D015232:Dinoprostone / Q000009:adverse effects*; D004347:Drug Interactions; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007213:Indomethacin / Q000008:administration & dosage; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage / Q000172:deficiency / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D011957:Receptors, Opioid / Q000008:administration & dosage / Q000172:deficiency / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013722:Teprotide / Q000008:administration & dosage; D013997:Time Factors; D014110:Touch; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000634:Aminoquinolines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D015232:Dinoprostone; D007213:Indomethacin; D009569:Nitric Oxide; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013722:Teprotide; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C000722287:Oprl1 protein, mouse