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Cholecystokinin receptor mechanism(s) and morphine tolerance in mice
M R Zarrindast1, S Nikfar, M Rezayat
1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran.
Abstract:
In a previous work, the effects of cholecystokinin receptor agonists on tolerance to morphine antinociception were evaluated. In the present study, the influence of cholecystokinin antagonists on the inhibition of tolerance to morphine antinociception by cholecystokinin agonists has been investigated. Maximum tolerance to morphine antinociception was obtained by morphine administration (50 mg/kg) to mice once daily for 4 days. The cholecystokinin receptor agonists caerulein (0.005 mg/kg) or cholecystokinin-8 (0.01 mg/kg) but not unsulfated cholecystokinin-8 (0.01 mg/kg) decreased the development of tolerance to morphine (9 mg/kg). The cholecystokininA receptor antagonist MK-329 (1 mg/kg) or the cholecystokininB receptor antagonist L-365,260 (0.25, 0.5 and 1 mg/kg) also diminished the tolerance to morphine antinociception. When animals were challenged with different doses of MK-329 (0.25, 0.5 and 1 mg/kg) against cholecystokinin-8 (0.01 mg/kg), caerulein (0.005 mg/kg) or unsulfated cholecystokinin-8 (0.01 mg/kg) on day 4 in tolerant mice, different response were obtained. Higher doses of MK-329 (1 mg/kg) caused a small decrease in attenuation of the morphine tolerance induced by cholecystokinin-8 and caerulein. Low doses of L-365, 260 diminished the effect of cholecystokinin-8 on morphine tolerance. Conversely high doses of the drug potentiated the response of caerulein (0.005 mg/kg). When animals were treated with MK-329 or L-365,260 before unsulfated cholecystokinin-8, reduction of the tolerance to morphine antinociception was obtained. These data indicate that both cholecystokinin receptors may modulate morphine tolerance.
Insights
Cholecystokinin (CCK) antagonists, MK-329 and L-365,260, were found to inhibit morphine tolerance in mice. These findings suggest that both CCK-A and CCK-B receptors play a role in modulating morphine antinociception tolerance.
Area of Science:
- Pharmacology
- Neuroscience
Background:
- Morphine tolerance, a decrease in antinociceptive effect with repeated administration, is a significant clinical challenge.
- Cholecystokinin (CCK) receptor agonists have previously been shown to affect morphine tolerance.
Purpose of the Study:
- To investigate the influence of CCK antagonists on the inhibition of morphine tolerance by CCK agonists.
- To determine the role of CCK-A and CCK-B receptors in modulating morphine tolerance.
Main Methods:
- Maximal morphine tolerance was induced in mice via daily morphine administration for 4 days.
- The effects of CCK agonists (caerulein, cholecystokinin-8) and antagonists (MK-329, L-365,260) on morphine tolerance were evaluated.
- Animals were challenged with varying doses of CCK antagonists in combination with CCK agonists.
Main Results:
- CCK agonists (caerulein, cholecystokinin-8) decreased morphine tolerance development.
- CCK-A antagonist MK-329 and CCK-B antagonist L-365,260 also diminished morphine tolerance.
- Dose-dependent effects were observed, with low doses of L-365,260 diminishing CCK-8's effect, while high doses potentiated caerulein's effect.
- Pre-treatment with CCK antagonists before unsulfated cholecystokinin-8 reduced morphine tolerance.
Conclusions:
- Both CCK-A and CCK-B receptors appear to modulate morphine tolerance.
- CCK antagonists represent a potential therapeutic strategy to mitigate opioid tolerance.