title: On the mechanism by which midazolam causes spinally mediated analgesia.
abstract: The electrical current thresholds for pain (ECTP) in the skin of the neck and tail were measured in rats with chronically implanted lumbar subarachnoid catheters. The effects of a benzodiazepine antagonist and a gamma-aminobutyric acid (GABA) antagonist on the analgesic effects of equivalent doses of midazolam, fentanyl, and ketocyclazocine were studied. These were the minimum doses producing maximal segmental analgesia when given intrathecally (i.e., they all caused a significant and maximum increase in ECTP in the tail, which was similar for all three drugs, but no significant change in the ECTP in the neck). Flumazenil (Ro 15-1788) administration caused a parallel shift to the right of the dose-response curve for midazolam spinal analgesia. Segmental analgesia following midazolam was also significantly attenuated (P less than 0.05) when the selective GABA antagonist bicuculline was given intrathecally at the same time as midazolam. The highest dose of bicuculline used (50 pmol) caused no significant attenuation of the segmental analgesic effects of either ketocyclazocine or fentanyl. The authors concluded that the segmental analgesia produced by intrathecal midazolam is mediated by the benzodiazepine-GABA receptor complex that is involved in other benzodiazepine actions.
authors.affiliation: Department of Pharmacology, University of Leeds, England.
authors.forename: M
authors.initials: M
authors.lastname: Edwards
authors.forename: J M
authors.initials: JM
authors.lastname: Serrao
authors.forename: J P
authors.initials: JP
authors.lastname: Gent
authors.forename: C S
authors.initials: CS
authors.lastname: Goodchild
mesh_terms: D015360:Analgesia, Epidural; D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003496:Cyclazocine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D016314:Ethylketocyclazocine / Q000031:analogs & derivatives*; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D012684:Sensory Thresholds / Q000187:drug effects
chemical_list: D011963:Receptors, GABA-A; C017069:bicuculline methiodide; D005442:Flumazenil; D016314:Ethylketocyclazocine; C012395:ketazocine; D003496:Cyclazocine; D008874:Midazolam; D005283:Fentanyl; D001640:Bicuculline