title: Spinal antinociceptive action of amiloride and its interaction with tizanidine in the rat formalin test.
abstract: BACKGROUND
  Amiloride has been reported to produce a wide variety of actions, thereby affecting several ionic channels and a multitude of receptors and enzymes. Intrathecal α2-adrenergic receptor agonists produce pronounced analgesia, and amiloride modulates α2-adrenergic receptor agonist binding and function, acting via the allosteric site on the α2A-adrenergic receptor.
  
  
  OBJECTIVE
  To investigate the antinociceptive interaction of intrathecal amiloride and the α2-adrenoceptor agonist tizanidine using a rat formalin test.
  
  
  METHODS
  Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters and were tested for paw flinching using formalin injection. Biphasic painful behaviour was recorded. Amiloride, tizanidine or an amiloride-tizanidine mixture was administered 10 min before formalin injection. To characterize any interactions, isobolographic analysis was performed. The effects of a pretreatment using intrathecally administered yohimbine was also tested.
  
  
  RESULTS
  Intrathecally administered amiloride (12.5 μg to 100 μg) and tizanidine (0.5 μg to 5 μg), given separately, produced a significant dose-related suppression of the biphasic responses in the formalin test. Isobolographic analysis revealed that the combination of intrathecal amiloride and tizanidine synergistically reduced phase I and II activities. Intrathecally administered yohimbine antagonized or attenuated the antinociceptive effect of amiloride, tizanidine and the amiloride-tizanidine mixture. Intrathecally administered amiloride synergistically interacts with tizanidine to reduce the nociceptive response in the formalin test, most likely by activating α2-adrenoceptors in the spinal cord.
  
  
  CONCLUSIONS
  Although intrathecal tizanidine produced pronounced analgesia, antinociceptive doses of intrathecal tizanidine also produced several side effects, including bradycardia and sedation. Amiloride produced antinociceptive action against the thermal nociceptive test without side effects in rats.
authors.forename: Handong
authors.initials: H
authors.lastname: Ouyang
authors.forename: Peizong
authors.initials: P
authors.lastname: Wang
authors.forename: Wan
authors.initials: W
authors.lastname: Huang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Bilin
authors.initials: B
authors.lastname: Nie
authors.forename: Weian
authors.initials: W
authors.lastname: Zeng
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use; D000584:Amiloride / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000316:Adrenergic alpha-Agonists; D000700:Analgesics; C023754:tizanidine; D000584:Amiloride; D003000:Clonidine