title: Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent.
abstract: SO-3, a novel Omega-superfamily conotoxin derived from Conus striatus, selectively inhibits N-type neuronal voltage-sensitive calcium channels. In current study, antinociception of SO-3 compared with MVIIA or morphine and its effects on morphine analgesia were investigated in rodent chemical stimulus tests after acute or repeated intrathecal administration. In mice acetic acid writhing test, similar to MVIIA, SO-3 caused dose- and time-dependent spinal antinociception with ED(50) of 0.25 microg/kg and t(1/2) of 4h, which was more potent and longer-acting than morphine. In rat formalin test after intrathecal bolus injection, SO-3 produced dose- and time-dependent antinociception by suppressing acute (ED(50), 1.79 microg/kg) and tonic phases (ED(50), 0.41 microg/kg), which was similar to MVIIA and approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses. After repeated intrathecal injections twice daily for 5 consecutive days, SO-3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test; further, SO-3 still produced potent analgesia in morphine-tolerant rats. SO-3 co-administered with morphine left-shift the dose-response curve of morphine in mice acetic acid writhing test and significantly potentiated morphine analgesia in rat formalin test. No changes in motor function were seen in mice or rats receiving antinociceptive doses of SO-3 whereas MVIIA caused motor dysfunction at doses of 1.0-2.0 microg/kg in rats. This study showed that (1) novel SO-3 produced potent and long-acting spinal antinociception without observable motor dysfunction, (2) SO-3 significantly potentiated morphine analgesia, (3) After repeated intrathecal administration, SO-3 produced neither tolerance nor cross-tolerance to morphine analgesia.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Haidian District, Beijing 100850, China.
authors.forename: Ling-Di
authors.initials: LD
authors.lastname: Yan
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Hua-Jin
authors.initials: HJ
authors.lastname: Dong
authors.forename: Pei-Lan
authors.initials: PL
authors.lastname: Zhou
authors.forename: Rui-Bin
authors.initials: RB
authors.lastname: Su
authors.forename: Ze-Hui
authors.initials: ZH
authors.lastname: Gong
authors.forename: Pei-Tang
authors.initials: PT
authors.lastname: Huang
mesh_terms: D019342:Acetic Acid / Q000633:toxicity; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D004347:Drug Interactions; D005557:Formaldehyde / Q000633:toxicity; D007278:Injections, Spinal; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D020960:omega-Conotoxins / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020960:omega-Conotoxins; D005557:Formaldehyde; D009020:Morphine; D019342:Acetic Acid