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Sensitivity to morphine-evoked bradycardia in rats is modified by dynorphin (1-13), Leu- and Met-enkephalin
Abstract:
Intravenous injection of morphine evokes, in the rat, a vagal chemoreflex resulting in bradycardia, hypotension and transient apnea. The morphine ED50 for producing bradycardia was utilized here as an index of the sensitivity to opioid stimulation of the organism. The potency of morphine for producing bradycardia can be modified by dynorphin (1-13), Leu- and Met-enkephalin. Both dynorphin (1-13) and Leu-enkephalin administered s.c. to normal and morphine-tolerant rats, 30 min before blood vessel cannulation and testing, lowered the morphine ED50 for bradycardia. Dynorphin (1-13) was 3 times more potent than Leu-enkephalin. Under the same test conditions, Met-enkephalin, given s.c. (0.45-0.9 mumol/kg) 30 min before morphine challenge, produced only desensitization to morphine-evoked bradycardia. The effects of dynorphin (1-13) were biphasic with respect to time of injection. When dynorphin (1-13) (0.3 mumol/kg s.c.) was injected s.c. 2 hr before morphine challenge, animals were desensitized to morphine by 2.5 times. Dynorphin (1-13) (0.19-0.77 nmol/hr s.c.) co-infused with morphine (74 nmol/hr s.c.) for 2 days accelerated tolerance development to morphine bradycardia. These results confirm previous studies which suggest that opioid peptides having Leu- or Met-enkephalin at its N-terminus manifest different pharmacological properties in vivo.
Insights
Opioid peptides dynorphin (1-13) and Leu-enkephalin can alter morphine sensitivity in rats. Dynorphin (1-13) showed biphasic effects, either increasing or decreasing sensitivity depending on administration timing.
Area of Science:
- Pharmacology
- Neuroscience
- Opioid Research
Background:
- Morphine induces a vagal chemoreflex in rats, causing bradycardia, hypotension, and apnea.
- The median effective dose (ED50) of morphine for bradycardia serves as an indicator of opioid sensitivity.
- Opioid peptides like dynorphin (1-13), Leu-enkephalin, and Met-enkephalin can modulate morphine's effects.
Purpose of the Study:
- To investigate how dynorphin (1-13), Leu-enkephalin, and Met-enkephalin affect morphine's potency in inducing bradycardia in rats.
- To explore the time-dependent and tolerance-related effects of dynorphin (1-13) on morphine-evoked bradycardia.
Main Methods:
- Rats were administered dynorphin (1-13), Leu-enkephalin, or Met-enkephalin subcutaneously before morphine challenge.
- Morphine ED50 for bradycardia was determined in normal and morphine-tolerant rats.
- Dynorphin (1-13) was administered at different time points and durations relative to morphine administration.
Main Results:
- Dynorphin (1-13) and Leu-enkephalin, administered 30 minutes before morphine, decreased the morphine ED50 for bradycardia, indicating increased sensitivity.
- Dynorphin (1-13) was three times more potent than Leu-enkephalin in this regard.
- Met-enkephalin administration resulted in desensitization to morphine-evoked bradycardia.
- Administering dynorphin (1-13) 2 hours before morphine led to a 2.5-fold desensitization.
- Co-infusion of dynorphin (1-13) with morphine accelerated the development of tolerance to morphine-induced bradycardia.
Conclusions:
- Opioid peptides with Leu- or Met-enkephalin at their N-terminus exhibit distinct in vivo pharmacological properties.
- Dynorphin (1-13) demonstrates biphasic effects on morphine sensitivity, influenced by administration timing.
- These findings highlight the complex interactions between different opioid peptides in modulating opioid responses and tolerance development.