Abstract
The mechanistic similarity between acutely and chronically induced morphine tolerance has been previously proposed but remains largely unexplored. Our experiments examined the modulation of acutely induced tolerance to spinally administered morphine by agonists that affect the N-methyl-d-aspartate receptor and nitric oxide synthase systems. Antinociception was detected via the hot water (52.5°C) tail flick test in mice. Intrathecal pretreatment with morphine (40 nmol) produced a 9.6-fold rightward shift in the morphine dose-response curve. This shift confirmed the induction of acute spinal morphine tolerance. Intrathecal copretreatment with the receptor antagonists (competitive and noncompetitive, respectively) dizolcipine (MK801, 3 nmol) or LY235959 (4 pmol) and morphine [40 nmol, intrathecally (i.t.)] attenuated acute tolerance to morphine measured 8 hr later. A 60-min pretreatment of 7-nitroindazole (6 nmol, i.t.), a selective neuronal NOS inhibitor, followed by administration of morphine (40 nmol, i.t.) blocked the induction of morphine tolerance. Intrathecal copretreatment with morphine (40 nmol, i.t.) and agmatine (4 nmol, i.t.), an imidazoline1 receptor agonist and putative nitric oxide synthase inhibitor, almost completely abolished acute spinal morphine tolerance. The results of these experiments agree with previous reports using models of chronically induced morphine tolerance. This evidence supports the proposal that the mechanisms responsible for acute morphine tolerance parallel those underlying chronic morphine tolerance. This study attests to the powerful predictive value of acute induction as a model for morphine tolerance.
Footnotes
-
Send reprint requests to: Dr. George L. Wilcox, Department of Pharmacology, 3-249 Millard Hall, 435 Delaware St. SE, Minneapolis, MN 55455.
-
↵1 This work was supported by NIH/K02-DA-00145 and NIH/R01-DA-04274 and ADAMHA training Grant T32A07234 awarded by NIDA.
- Abbreviations:
- ANOVA
- analysis of variance
- CREB
- cAMP-responsive element-binding protein
- I1
- imidazoline1
- i.t.
- intrathecal(ly)
- l-NNA
- l-NG-nitro-l-arginine
- l-NAME
- l-NG-nitro-l-arginine methyl ester
- LY
- LY235959
- MK801
- dizolcipine
- % MPE
- percent maximum possible effect
- NMMA
- NG-monomethyl-l-arginine
- NO2Arg
- NG-nitro-l-arginine
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- 7-NI
- 7-nitroindazole
- NMDA
- N-methyl-d-aspartate
- pmol
- picomoles
- PKC
- protein kinase C
- Received October 7, 1996.
- Accepted May 2, 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.
|
