Abstract
Rats were made tolerant to the hypnotic effects of thealpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [3H]PN200–110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [3H]PN200–110. An increase inBmax for [3H]PN200–110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 μg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.
Footnotes
-
Send reprint requests to: Mervyn Maze, M.B., Anesthesiology Service (112A), Veterans Administration Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304.
-
↵1 This work was supported by National Institutes of Health and the Department of Veterans Affairs.
- Abbreviations:
- ANOVA
- analysis of variance
- Bmax
- receptor density
- cAMP
- cyclic adenosine monophosphate
- LC
- locus ceruleus
- LORR
- loss of righting reflex
- PKA
- protein kinase A
- PTX
- pertussis toxin
- TTX
- tetrodotoxin
- Received December 13, 1996.
- Accepted July 30, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|