title: Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats.
abstract: BACKGROUND
  Tolerance to the analgesic effect of opioids complicates the management of persistent pain states. We tested whether the intrathecal infusion of small interfering RNA (siRNA) against β-arrestin 2 would reduce tolerance to chronic morphine use and the severity of precipitated morphine withdrawal.
  
  
  METHODS
  Intrathecal β-arrestin 2 (2 μg siRNA per 10 μl per rat) was injected once daily for 3 days. Rats then received a continuous intrathecal infusion of morphine (2 nmol h⁻¹) or saline for 7 days. Daily tail-flick (TF) and intrathecal morphine challenge tests were performed to assess the effect of intrathecal β-arrestin 2 siRNA on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg kg⁻¹) was performed to assess morphine dependence.
  
  
  RESULTS
  In the daily TF test, the antinociception of intrathecal morphine was increased and maintained in rats receiving β-arrestin 2 siRNA compared with the control group (morphine alone). In the probe response test, rats receiving morphine infusion with β-arrestin 2 siRNA treatment showed a significant left shift in their dose-response curve, as measured by per cent maximal possible effect (MPE), such that the AD₅₀ was significantly decreased by a factor of 5.6 when compared with that of morphine-infused rats. In the naloxone-induced withdrawal tests, rats receiving β-arrestin 2 siRNA injection with morphine infusion showed a significant reduction in four of the six signs of withdrawal.
  
  
  CONCLUSIONS
  We show here that intrathecal β-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.
authors.affiliation: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Niao-Sung District, Kaohsiung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Yang
authors.forename: H-W
authors.initials: HW
authors.lastname: Huang
authors.forename: K-H
authors.initials: KH
authors.lastname: Chen
authors.forename: Y-S
authors.initials: YS
authors.lastname: Chen
authors.forename: S-M
authors.initials: SM
authors.lastname: Sheen-Chen
authors.forename: C-R
authors.initials: CR
authors.lastname: Lin
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000503:physiopathology; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; C000605257:Arrb2 protein, rat; D019390:Arrestins; D009292:Narcotic Antagonists; D034741:RNA, Small Interfering; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009270:Naloxone; D012965:Sodium Chloride; D009020:Morphine