Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances

Eur J Pharmacol. 1988 Feb 9;146(2-3):223-8. doi: 10.1016/0014-2999(88)90296-8.


Clonidine analgesia was tested on the hyperalgesia induced by intraplantar injection of prostaglandin E2 or carrageenin. The antinociceptive effect of clonidine was dose-dependent and was abolished by local administration of the selective alpha 2-adrenoceptor blocker, yohimbine or of the opioid antagonists naloxone or quaternary nalorphine. St-91, a clonidine analog which does not cross the blood-brain barrier also promoted significant antinociception. Repeated administration of drugs possessing a central mechanism of analgesic action leads to the development of tolerance in this test. Significant analgesic tolerance was observed following repeated (5 days) morphine (8 mg/kg) or high doses of clonidine (0.5 mg/kg). In contrast, no tolerance was detected to the analgesic effect of low doses of clonidine (0.15 mg/kg) or of St-91 (0.5 mg/kg). These results suggest that, in addition to its central analgesic action, clonidine can induce peripheral antinociception by an alpha 2-adrenoceptor-mediated local release of enkephalin-like substances.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics*
  • Animals
  • Carrageenan / pharmacology
  • Clonidine / antagonists & inhibitors
  • Clonidine / pharmacology*
  • Dinoprostone
  • Drug Tolerance
  • Enkephalins / metabolism*
  • Male
  • Morphine / pharmacology
  • Naloxone / pharmacology
  • Peripheral Nerves / drug effects*
  • Prostaglandins E / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Yohimbine / pharmacology


  • Analgesics
  • Enkephalins
  • Prostaglandins E
  • Yohimbine
  • Naloxone
  • Morphine
  • Carrageenan
  • Dinoprostone
  • Clonidine