Tolerance to morphine bradycardia in the rat

Area of Science:

• Pharmacology
• Neuroscience
• Cardiovascular Physiology

Background:

• Opiate agonists administered intravenously induce a rapid but transient decrease in heart rate in rats.
• This bradycardia is hypothesized to be a vagal chemoreflex originating from peripheral opiate receptors.

Purpose of the Study:

• To investigate the peripheral origin of opiate-induced bradycardia.
• To explore the development of tolerance to this peripheral effect.
• To assess the utility of vagal bradycardia as an index for studying peripheral opioid actions.

Main Methods:

• Intravenous and central injections of opiate agonists in rats.
• Administration of naloxone to block bradycardia.
• Subcutaneous and central infusions of morphine sulfate to induce tolerance.
• Cross-tolerance studies with an enkephalin analog (FK33,824) and other agonists.

Main Results:

• Peripheral administration of morphine resulted in faster onset bradycardia compared to central administration.
• Intravenous naloxone blocked bradycardia effectively at doses ineffective centrally.
• Tolerance to morphine-induced bradycardia developed after subcutaneous, but not central, morphine infusions.
• Cross-tolerance was observed between morphine and FK33,824, but not serotonin or phenyldiguanide.

Conclusions:

• Opiate-induced bradycardia in rats is primarily mediated by peripheral opiate receptors.
• Tolerance to peripheral opioid effects differs from central tolerance.
• Vagal bradycardia serves as a valuable and convenient model for investigating peripheral opioid receptor pharmacology.