Sodium butyrate and its synthetic amide derivative modulate nociceptive behaviors in mice

Pharmacol Res. 2016 Jan;103:279-91. doi: 10.1016/j.phrs.2015.11.026. Epub 2015 Dec 8.

Abstract

In the present study we investigated the role of sodium butyrate (butyrate), and its more palatable derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), in animal models of acute and chronic pain. We found that oral administrations of butyrate (10-200mg/Kg) or equimolecular FBA (21.2-424mg/Kg) reduced visceral pain in a dose- and time-dependent manner. Both drugs were also effective in the formalin test, showing an antinociceptive effect. This analgesic effect was blocked by glibenclamide, suggesting the involvement of ATP-dependent K(+) channels. Moreover, following repeated administration butyrate (100-200mg/Kg) and FBA (212-424mg/Kg) retained their analgesic properties in a model of neuropathic pain, reducing mechanical and thermal hyperalgesia in the chronic constriction injury (CCI) model. The involvement of peroxisome proliferator-activated receptor (PPAR) -α and -γ for the analgesic effect of butyrate was also investigated by using PPAR-α null mice or the PPAR-γ antagonist GW9662. Western blot analysis, confirmed the role of peroxisome receptors in butyrate effects, evidencing the increase of PPAR-α and -γ expression, associated to the reduction of inflammatory markers (COX-2, iNOS, TNF-α and cFOS). In conclusion, we describe the role of butyrate-based drugs in pain, identifying different and converging non-genomic and genomic mechanisms of action, which cooperate in nociception maintenance.

Keywords: ATP-dependent K+ channel; Chronic constriction injury (CCI); Formalin test; Inflammation; Nociception; Peroxisome proliferator-activated receptor; Sodium butyrate; Visceral pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetic Acid
  • Amides / pharmacology*
  • Amides / therapeutic use
  • Analgesics / pharmacology*
  • Analgesics / therapeutic use
  • Anilides / pharmacology
  • Animals
  • Butyric Acid / pharmacology*
  • Butyric Acid / therapeutic use
  • Formaldehyde
  • Hot Temperature
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Kaolin
  • Magnesium Sulfate
  • Male
  • Mice
  • Mice, Knockout
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism
  • Pain / drug therapy
  • Pain / metabolism*
  • Physical Stimulation
  • Sciatic Nerve / injuries
  • Spinal Cord / metabolism

Substances

  • 2-chloro-5-nitrobenzanilide
  • Amides
  • Analgesics
  • Anilides
  • PPAR alpha
  • PPAR gamma
  • Butyric Acid
  • Formaldehyde
  • Kaolin
  • Magnesium Sulfate
  • Acetic Acid