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The response of the intestinal mucosa to prostaglandin E2 during withdrawal from morphine
I M Coupar1, J Hardcastle, P T Hardcastle
1Unit of Addictive Drug Research, School of Pharmacology, Victorian College of Pharmacy, Parkville, Australia.
Abstract:
Experiments were designed to determine whether the diarrhoea characteristic of morphine withdrawal results from an enhanced sensitivity of the intestinal mucosa to PGE2. Rats (250-300 g) were made morphine-dependent by subcutaneous injection of an emulsion releasing 300 mg morphine HCl over 48 h. In-vivo, the transintestinal potential difference (PD) responses to PGE2 (4.6-46 micrograms kg-1 i.v.), which reflect increased Cl secretion, were significantly larger in withdrawn (morphine emulsion, 10 mg kg-1 naloxone s.c.) compared with non-dependent animals (emulsion only, naloxone s.c., P less than 0.05). Muscle-stripped intestinal sheets from dependent animals incubated with naloxone (10(-5) mol L-1) in-vitro did not demonstrate a greater electrical response (PD, short circuit current) to PGE2 (1.4 x 10(-6) mol L-1) than sheets taken from non-dependent animals. In-vitro preparations from animals withdrawn in-vivo did not respond differently from tissue taken from non-dependent animals (naloxone 10 mg kg-1 s.c., 10(-4) mol L-1 in medium, in both groups). This occurred in whole sheets of intestine as well as sheets without attached muscle. Jejunal fluid absorption in-vivo was lower in withdrawn animals than in non-dependent animals. However, the responses to intra-arterial infusion of PGE2 were similar in both groups with 2 micrograms min-1 inhibiting absorption and 4 micrograms min-1 inducing secretion. In-vivo, PGE2-induced Cl secretion appears to be enhanced during withdrawal although net fluid transport is not altered, suggesting different effects of the withdrawal process on the electrogenic Cl secretory and neutral NaCl absorptive mechanisms.
Insights
Morphine withdrawal enhances intestinal sensitivity to prostaglandin E2 (PGE2) in vivo, leading to increased chloride secretion but not altered net fluid transport. This suggests withdrawal impacts specific intestinal mechanisms differently.
Area of Science:
- Gastroenterology
- Pharmacology
- Physiology
Background:
- Diarrhea is a common symptom of morphine withdrawal.
- Prostaglandin E2 (PGE2) plays a role in intestinal fluid and electrolyte transport.
- The role of PGE2 sensitivity in morphine withdrawal-induced diarrhea is not fully understood.
Purpose of the Study:
- To investigate whether morphine withdrawal enhances intestinal sensitivity to PGE2.
- To determine the in vivo and in vitro effects of PGE2 on intestinal transport during morphine withdrawal.
Main Methods:
- Morphine dependence was induced in rats using a subcutaneous emulsion.
- In vivo transintestinal potential difference (PD) and jejunal fluid absorption were measured.
- In vitro electrical responses (PD, short circuit current) of intestinal sheets to PGE2 were assessed.
- Naloxone was used to precipitate withdrawal in vivo and in vitro.
Main Results:
- In vivo, withdrawn rats showed significantly larger PD responses to intravenous PGE2 compared to non-dependent rats.
- In vitro, intestinal sheets from withdrawn and non-dependent rats exhibited similar electrical responses to PGE2.
- In vivo, jejunal fluid absorption was lower in withdrawn rats, but PGE2 responses were similar in both groups, inhibiting absorption or inducing secretion at specific doses.
- In vivo PGE2-induced chloride secretion was enhanced during withdrawal, while net fluid transport remained unchanged.
Conclusions:
- Morphine withdrawal enhances in vivo intestinal sensitivity to PGE2, specifically affecting electrogenic chloride secretion.
- The observed effects suggest differential impacts of morphine withdrawal on intestinal absorptive and secretory mechanisms.
- These findings contribute to understanding the pathophysiology of morphine withdrawal-induced diarrhea.