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Nitric oxide and opioid tolerance
A M Babey1, Y Kolesnikov, J Cheng
1Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Abstract:
Under conditions in which NG-nitro-L-arginine (NOArg) treatment prevents morphine tolerance, NOArg induces a slow progressive inhibition of nitric oxide synthase (NOS), starting at approx. 20% after a single treatment and increasing to approx. 65% after 10 days. Studies designed to examine potential changes in NOS levels with chronic morphine administration reveal no change. Total NOS activity in both brainstem and cerebellum homogenates is unchanged, as are levels of NOS mRNA in a variety of brain regions. L-Arginine, the precursor of nitric oxide (NO), accelerates tolerance when coadministered with morphine and when given alone L-arginine decreases morphine's potency. Administration of L-arginine alone for 3-10 days shifts morphine's dose-response curve over 2-fold to the right while D-arginine is without effect, as is daily administration of L-arginine along with the NOS inhibitor NOArg. Thus, chronic L-arginine induces "tolerance" in opioid naive mice through NOS. Together, our data indicate an important role for NO in the modulation of opioid analgesia.
Insights
Nitric oxide synthase (NOS) inhibition prevents morphine tolerance. Chronic L-arginine administration induces tolerance in opioid-naive mice by activating NOS, highlighting NO's role in opioid analgesia.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Morphine tolerance is a significant clinical challenge.
- The role of nitric oxide (NO) in opioid analgesia is not fully understood.
Purpose of the Study:
- To investigate the role of nitric oxide synthase (NOS) and its substrate L-arginine in the development of morphine tolerance.
- To explore the potential of modulating NOS activity for pain management.
Main Methods:
- Administered NG-nitro-L-arginine (NOArg), a NOS inhibitor, and L-arginine to mice.
- Assessed changes in NOS activity and mRNA levels.
- Evaluated morphine's analgesic potency using dose-response curves.
Main Results:
- NOArg treatment prevented morphine tolerance and progressively inhibited NOS activity.
- Chronic morphine administration did not alter NOS levels or activity.
- L-arginine administration alone accelerated morphine tolerance and decreased morphine potency.
- Chronic L-arginine induced tolerance in opioid-naive mice via NOS.
Conclusions:
- Nitric oxide plays a crucial role in modulating opioid analgesia.
- Targeting NOS activity presents a potential strategy for managing opioid tolerance.