Short small-interfering RNAs produce interferon-α-mediated analgesia

Br J Anaesth. 2012 Apr;108(4):662-9. doi: 10.1093/bja/aer492. Epub 2012 Feb 3.

Abstract

Background: There is increasing interest in RNA interference in pain research using the intrathecal route to deliver small-interfering RNA (siRNA). An interferon (IFN) response is a common side-effect of siRNA. However, the IFN response in the spinal cord after intrathecal administration of siRNA remains unknown. We hypothesized that high doses of siRNAs can elicit off-target analgesia via releasing IFN-α. We investigated the IFN response and its role in regulating pain sensitivity in the spinal cords after intrathecal administration of siRNAs.

Methods: Male Sprague-Dawley rats were given intrathecal injections of non-targeting (NT) siRNAs or IFN-α and tested for complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. IFN-α in the spinal cord after injection of NT siRNAs was measured by western blotting and immunohistochemical staining.

Results: IFN-α was up-regulated in the spinal cord after intrathecal treatment of NT siRNAs. Intrathecal injection of NT siRNAs, at high doses of 10 or 20 μg, reduced CFA-induced inflammatory pain (P<0.05). Intrathecal application of IFN-α inhibited pain hypersensitivity in inflamed rats and produced analgesia in naïve rats (P<0.05). Notably, the anti-nociceptive effects elicited by NT siRNAs and IFN-α were reversed by IFN-α neutralizing antibody and naloxone.

Conclusions: Our data suggest that (i) intrathecal administration of high doses of siRNA (≥ 10 μg) induced up-regulation of IFN-α in the spinal cord and produced analgesic effects through IFN-α, and (ii) IFN-α's analgesic effect is mediated via opioid receptors. Caution must be taken to avoid IFN-α-mediated analgesic effects of siRNAs in pain research.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods*
  • Animals
  • Blotting, Western
  • Disease Models, Animal
  • Freund's Adjuvant / administration & dosage
  • Freund's Adjuvant / pharmacology
  • Hyperalgesia / drug therapy
  • Immunologic Factors / pharmacology
  • Inflammation / complications
  • Inflammation / drug therapy
  • Injections, Spinal
  • Interferon-alpha / administration & dosage
  • Interferon-alpha / pharmacology*
  • Male
  • Pain / complications
  • Pain / drug therapy*
  • Pain Management / methods
  • Pain Threshold / drug effects
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Up-Regulation / drug effects

Substances

  • Immunologic Factors
  • Interferon-alpha
  • RNA, Small Interfering
  • Freund's Adjuvant