title: Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons.
abstract: The nociceptin/orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand nociceptin/orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry and assessed functional effects of NOP and μ-opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder suburothelium revealed a remarkable several-fold increase in detrusor overactivity (P < 0.0001) and painful bladder syndrome patient specimens (P = 0.0014) compared with controls. In postmortem control human DRG, 75% to 80% of small/medium neurons (≤50 μm diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP immunoreactivity was significantly decreased in injured peripheral nerves (P = 0.0004), and also in painful neuromas (P = 0.025). Calcium-imaging studies in cultured rat DRG neurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (P < 0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than μ-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials.
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Yiangos
authors.initials: Y
authors.lastname: Yiangou
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Uma
authors.initials: U
authors.lastname: Anand
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Mukerji
authors.affiliation: Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Sinisi
authors.affiliation: Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Fox
authors.affiliation: Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: McQuillan
authors.affiliation: Peripheral Nerve Injury Unit, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Quick
authors.affiliation: Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Korchev
authors.affiliation: Grünenthal Innovation, Translational Science and Strategy, Grünenthal GmbH, Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hein
mesh_terms: D000818:Animals; D020516:Brachial Plexus Neuropathies / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D018856:Cystitis, Interstitial / Q000473:pathology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D009463:Neuroma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018847:Opioid Peptides / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000473:pathology*; D064531:Peripherins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000473:pathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D002118:Calcium; D061207:Calcium Ionophores; D002211:Capsaicin; D015759:Ionomycin; D018847:Opioid Peptides; D064531:Peripherins; D011957:Receptors, Opioid; D050916:TRPV Cation Channels; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C579004:Prph protein, rat; C494482:TRPV1 protein, human