title: Selective depression of nociceptive responses of dorsal horn neurones by SNC 80 in a perfused hindquarter preparation of adult mouse.
abstract: Detailed electrophysiological characterisation of spinal opioid receptors in the mouse has been limited due to various technical difficulties. In this study, extracellular single unit recordings were made from dorsal horn neurones in a perfused spinal cord with attached trunk-hindquarter to investigate the role of delta-opioid receptor in mediating nociceptive and non-nociceptive transmission in mouse. Noxious electrical shock, pinch and heat stimuli evoked a mean response of 20.8+/-2.5 (n=10, P<0.005), 30.1+/-5.4 (n=58, P<0.005) and 40.9+/-6.3 (n=29, P<0.005) spikes per stimulus respectively. In 5 of 22 cells, repetitive noxious electrical stimuli applied to the hindpaw for 20 s produced a progressive increase in spike number, the phenomenon known as 'wind-up' and/or hyperactivity. When the selective delta-opioid receptor agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) was perfused for 8-10 min, these evoked nociceptive responses were reversibly depressed. SNC 80 (2 microM) depressed the nociceptive responses evoked by electrical shock, pinch and heat by 74.0+/-13.7% (n=8, P<0.01), 66.5+/-16.6% (n=10, P<0.01) and 74.1+/-17.0% (n=10, P<0.01) respectively. The maximum depression by 5 microM SNC 80 was 92.6+/-6.8% (n=3). SNC 80 at 5 microM also completely abolished the wind-up and/or hypersensitivity (n=5). The depressant effects of SNC 80 on the nociceptive responses were completely blocked by 10 microM naloxone (n=5) and 3 microM 17-(cyclopropylmethyl)-6,7-dehydro-4,5 alpha-epoxy-14 beta-ethoxy-5 beta-methylindolo [2',3':6',7'] morphinan-3-ol hydrochloride (HS 378, n=8), a novel highly selective delta-opioid receptor antagonist. Interestingly, HS 378 (3 microM) itself potentiated the background activity and evoked responses to pinch and heat by 151.8+/-38.4% (P<0.05, n=8), 34.2+/-6.1% (P<0.01, n=7) and 45.5+/-11.8% (P<0.05, n=5) respectively. In contrast, the responses of non-nociceptive dorsal horn neurones were not inhibited by SNC 80 at a dose of up to 10 microM (n=5). These data demonstrate that delta-opioid receptor modulate nociceptive, but not non-nociceptive, transmission in spinal dorsal horn neurones of the adult mouse. The potentiation of neuronal activity by HS 378 may reflect an autoregulatory role of the endogenous delta-opioid in nociceptive transmission in mouse.
authors.affiliation: Department of Pharmacology, AstraZeneca R&D Montreal, 7171 Frederick-Banting, St-Laurent (Montreal), QC, Canada H4S 1Z9. changqing.cao@astrazeneca.com
authors.forename: C Q
authors.initials: CQ
authors.lastname: Cao
authors.forename: Y G
authors.initials: YG
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Dray
authors.forename: M N
authors.initials: MN
authors.lastname: Perkins
mesh_terms: D000200:Action Potentials; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010879:Piperazines / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000503:physiopathology; D017465:Receptors, Opioid, delta / Q000819:agonists*
chemical_list: D001549:Benzamides; C437947:HS 378; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009271:Naltrexone