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An implanted reservoir of morphine solution for rapid induction of physical dependence in rats
Abstract:
1. Rats were dosed continuously with morphine hydrochloride by giving a daily dose through tubes connected to small, subcutaneously implanted reservoirs. Morphine was withdrawn by washing out the reservoir with drug vehicle. The daily dose of morphine, or substitute drug received by each rat was determined by difference by estimating the drug remaining in reservoir washings.2. Withdrawal symptoms were more pronounced after 9 days than after 4 days of dosing with morphine.3. Body weight loss, maximal at 24 h, and increased defaecation during the first 7 h were the chief physiological signs of morphine withdrawal. The body weight loss was the result of hypodipsia and anorexia exacerbated by increased defaecation.4. When substituted for morphine in the reservoir, methadone and codeine completely prevented body weight loss and increased defaecation, while pethidine was effective against increased defaecation, but not against 24 h body weight loss. The opiate-antagonist analgesics pentazocine, nalorphine and cyclazocine either had no effect on withdrawal symptoms or increased their severity.5. In morphine dependent rats under continued morphine administration subcutaneous doses of the opiate-antagonists nalorphine, cyclazocine and naloxone all precipitated the withdrawal symptoms of body weight loss and increased defaecation. The weak antagonist pentazocine caused a significantly increased defaecation, but no significant change in body weight, while the opiates pethidine, codeine and methadone had no significant effect on body weight or defaecation.6. The advantages of inducing dependence by this method of dosing are discussed.
Insights
Continuous morphine dosing in rats revealed that methadone and codeine effectively alleviated withdrawal symptoms, unlike certain opiate antagonists which exacerbated them. This study offers insights into opioid dependence and withdrawal management.
Area of Science:
- Pharmacology
- Neuroscience
- Animal Models
Background:
- Opioid dependence and withdrawal are significant clinical challenges.
- Understanding the physiological manifestations of opioid withdrawal is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the physiological signs of morphine withdrawal in rats using a continuous dosing method.
- To evaluate the efficacy of various opioid agonists and antagonists in preventing or precipitating withdrawal symptoms.
Main Methods:
- Rats were continuously dosed with morphine hydrochloride via subcutaneously implanted reservoirs.
- Morphine withdrawal was induced by reservoir washout; drug doses were calculated by difference.
- Physiological signs, including body weight loss and defaecation, were monitored.
Main Results:
- Morphine withdrawal symptoms intensified after 9 days compared to 4 days.
- Methadone and codeine prevented body weight loss and increased defaecation; pethidine partially mitigated defaecation.
- Opiate antagonists (pentazocine, nalorphine, cyclazocine) either failed to alleviate or worsened withdrawal signs.
Conclusions:
- Continuous subcutaneous drug administration provides a reliable method for inducing and studying opioid dependence and withdrawal.
- Certain opioid agonists can effectively suppress morphine withdrawal symptoms.
- Opiate antagonists can precipitate or exacerbate withdrawal, highlighting their distinct pharmacological profiles.