title: Regulation of spinal substance p release by intrathecal calcium channel blockade.
abstract: BACKGROUND
  The authors investigated the role of different voltage-sensitive calcium channels expressed at presynaptic afferent terminals in substance P release and on nociceptive behavior evoked by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and L-type voltage-sensitive calcium channel blockers (diltiazem and verapamil).
  
  
  METHODS
  Rats received intrathecal pretreatment with saline or doses of morphine, ziconotide, mibefradil, diltiazem, or verapamil. The effect of these injections upon flinching evoked by intraplantar formalin (5%, 50 μl) was quantified. To assess substance P release, the incidence of neurokinin-1 receptor internalization in the ipsilateral and contralateral lamina I was determined in immunofluorescent-stained tissues.
  
  
  RESULTS
  Intrathecal morphine (20 μg), ziconotide (0.3, 0.6, and 1 μg), mibefradil (100 μg, but not 50 μg), diltiazem (500 μg, but not 300 μg), and verapamil (200 μg, but not 50 and 100 μg) reduced paw flinching in phase 2 compared with vehicle control (P < 0.05), with no effect on phase 1. Ziconotide (0.3, 0.6, and 1 μg) and morphine (20 μg) significantly inhibited neurokinin-1 receptor internalization (P < 0.05), but mibefradil, diltiazem, and verapamil at the highest doses had no effect.
  
  
  CONCLUSIONS
  These results emphasize the role in vivo of N-type but not T- and L-type voltage-sensitive calcium channel blockers in mediating the stimulus-evoked substance P release from small primary afferents and suggest that T- and L-type voltage-sensitive calcium channel blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving postsynaptic excitability.
authors.affiliation: Department of Anesthesiology, School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takasusuki
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects; D020747:Calcium Channels, T-Type / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009068:Movement / Q000187:drug effects; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D018040:Receptors, Neurokinin-1; D020960:omega-Conotoxins; D013373:Substance P; D009020:Morphine; C078452:ziconotide