title: Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test.
abstract: BACKGROUND
  Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level.
  
  
  METHODS
  Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction.
  
  
  RESULTS
  Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133).
  
  
  CONCLUSIONS
  Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwanju, Korea. mhyoon@chonnam.ac.kr
authors.forename: Myung Ha
authors.initials: MH
authors.lastname: Yoon
authors.forename: Jeong Il
authors.initials: JI
authors.lastname: Choi
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005557:Formaldehyde; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors
chemical_list: D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000970:Antineoplastic Agents; D048588:Benzoxazines; D002186:Cannabinoids; D002800:Cholinesterase Inhibitors; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005557:Formaldehyde; D009388:Neostigmine; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D003000:Clonidine; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline