Endogenous opioid and cannabinoid systems modulate the muscle pain: A pharmacological study into the peripheral site

Eur J Pharmacol. 2021 Jun 15:901:174089. doi: 10.1016/j.ejphar.2021.174089. Epub 2021 Apr 4.


The participation of the peripheral opioid and cannabinoid endogenous systems in modulating muscle pain and inflammation has not been fully explored. Thus, the aim of this study was to investigate the involvement of these endogenous systems during muscular-tissue hyperalgesia induced by inflammation. Hyperalgesia was induced by carrageenan injection into the tibialis anterior muscles of male Wistar rats. We padronized an available Randal-Sellito test adaptation to evaluate nociceptive behavior elicited by mechanical insult in muscles. Western blot analysis was performed to evaluate the expression levels of opioid and cannabinoid receptors in the dorsal root ganglia. The non-selective opioid peptide receptor antagonist (naloxone) and the selective mu opioid receptor MOP (clocinnamox) and kappa opioid receptor KOP (nor-binaltorphimine) antagonists were able to intensify carrageenan-induced muscular hyperalgesia. On the other hand, the selective delta opioid receptor (DOP) antagonist (naltrindole) did not present any effect on nociceptive behavior. Moreover, the selective inhibitor of aminopeptidases (Bestatin) provoked considerable dose-dependent analgesia when intramuscularly injected into the hyperalgesic muscle. The CB1 receptor antagonist (AM251), but not the CB2 receptor antagonist (AM630), intensified muscle hyperalgesia. All irreversible inhibitors of anandamide hydrolase (MAFP), the inhibitor for monoacylglycerol lipase (JZL184) and the anandamide reuptake inhibitor (VDM11) decreased carrageenan-induced hyperalgesia in muscular tissue. Lastly, MOP, KOP and CB1 expression levels in DRG were baseline even after muscular injection with carrageenan. The endogenous opioid and cannabinoid systems participate in peripheral muscle pain control through the activation of MOP, KOP and CB1 receptors.

Keywords: Cannabinoid; Muscle inflammation; Muscle pain; Opioid.

MeSH terms

  • Animals
  • Arachidonic Acids / antagonists & inhibitors
  • Carrageenan
  • Cinnamates / pharmacology
  • Endocannabinoids / antagonists & inhibitors
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / psychology
  • Male
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Morphine Derivatives / pharmacology
  • Myalgia / chemically induced
  • Myalgia / drug therapy*
  • Myalgia / psychology
  • Naloxone / pharmacology
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Pain Measurement / drug effects
  • Polyunsaturated Alkamides / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Receptors, Cannabinoid / drug effects
  • Receptors, Cannabinoid / physiology*
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / physiology*
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, kappa / drug effects
  • Receptors, Opioid, mu / drug effects


  • Arachidonic Acids
  • Cinnamates
  • Endocannabinoids
  • Morphine Derivatives
  • Polyunsaturated Alkamides
  • Receptors, Cannabinoid
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • binaltorphimine
  • clocinnamox
  • Naloxone
  • Naltrexone
  • Carrageenan
  • Monoacylglycerol Lipases
  • anandamide