title: The dissociation of sedative from spinal antinociceptive effects following administration of a novel alpha-2-adrenoceptor agonist, MPV-2426, in the locus coeruleus in the rat.
abstract: BACKGROUND
  MPV-2426 is a novel alpha-2-adrenoceptor agonist developed for spinal pain therapy. In the present study we characterized its sedative and antinociceptive properties following microinjections into the brainstem and intrathecally at the lumbar spinal cord level.
  
  
  METHODS
  Sedative effects of MPV-2426 were assessed in a locomotion measuring device following unilateral microinjection into the locus coeruleus (LC) of the brainstem or 1-2 mm rostral to the LC in rats. Antinociceptive effects induced by MPV-2426 in the brainstem, and for comparison intrathecally at the lumbar spinal cord level, were determined with a tail-flick test. Dexmedetomidine was used as the reference alpha-2-adrenoceptor agonist.
  
  
  RESULTS
  MPV-2426 produced a dose-related hypolocomotive/sedative effect, which was significantly stronger following microinjection into the LC than 1-2 mm rostral to the LC. The sedation induced by MPV-2426 was reversed by atipamezole (1 mg/kg s.c.), an alpha-2-adrenoceptor antagonist. The sedative potency of dexmedetomidine, the reference alpha-2-adrenoceptor agonist, was stronger and less dependent on the exact injection site in the brainstem. Following microinjections at sedative doses in the brainstem, only dexmedetomidine produced a significant antinociceptive effect in the tail-flick test. When microinjected into the lumbar spinal cord, MPV-2426 and dexmedetomidine had an equally strong antinociceptive effect in the tail-flick test.
  
  
  CONCLUSIONS
  The results indicate that the sedative potency of MPV-2426 is considerably weaker than that of dexmedetomidine. Additionally, the spread of MPV-2426 within the central nervous system is more limited than that of dexmedetomidine. This could explain why MPV-2426 is sedative only when injected into the LC while antinociceptive effect is obtained when it is injected intrathecally at the lumbar spinal cord level.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Wei
authors.forename: V K
authors.initials: VK
authors.lastname: Kontinen
authors.forename: E
authors.initials: E
authors.lastname: Kalso
authors.forename: A
authors.initials: A
authors.lastname: Pertovaara
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001143:Arousal / Q000187:drug effects; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D007189:Indans; D020927:Dexmedetomidine; C400294:radolmidine