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: C-H Yang, H-W Huang, K-H Chen, Y-S Chen, S-M Sheen-Chen, C-R Lin
• Journal: British journal of anaesthesia (Br J Anaesth) Vol. 107 Issue 5 Pg. 774-81 (Nov 2011) ISSN: 1471-6771 [Electronic] England
• PMID: 21926413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Arrb2 protein, rat
• Arrestins
• Narcotic Antagonists
• RNA, Small Interfering
• beta-Arrestin 2
• beta-Arrestins
• Naloxone
• Sodium Chloride
• Morphine

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Arrestins (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Drug Tolerance
• Injections, Spinal
• Male
• Morphine (pharmacology)
• Morphine Dependence (physiopathology)
• Naloxone (administration & dosage)
• Narcotic Antagonists (administration & dosage)
• Pain (drug therapy)
• Pain Measurement
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sodium Chloride (administration & dosage)
• Substance Withdrawal Syndrome (physiopathology)
• beta-Arrestin 2
• beta-Arrestins