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Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats
K Lutfy1, S M Hossain, I Khaliq
1Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, California, CA 90024, USA. klutfy@ucla.edu
Abstract:
1. Recent evidence from studies in mice lacking the opioid receptor-like (ORL-1) receptor and from experiments using antibodies raised against orphanin FQ/nociceptin (OFQ/N) suggest that this peptide may be involved in morphine tolerance. In the present study we sought to investigate if administration of exogenous OFQ/N would modulate the development of tolerance to the antinociceptive effect of morphine. 2. Rats were treated for 3 days with either saline or morphine (10 mg kg(-1), s.c.) followed, 15 and 75 min later, by two intracerebroventricular injections of either artificial cerebrospinal fluid (aCSF) or OFQ/N. The dose of OFQ/N was doubled each day (7.5, 15, 30 nmol). On day 4, rats were tested on a hot plate apparatus before and 30, 60 and 90 min after morphine administration. 3. Repeated OFQ/N treatment did not affect basal nociceptive responses or morphine-induced antinociception. However, the same treatment significantly attenuated the development of morphine tolerance. 4. Since learning and memory could contribute to the development of morphine tolerance, in subsequent studies, we examined the effect of OFQ/N administered in the CA3 region of the hippocampus, where OFQ/N has been shown to block LTP and impair spatial memory. A greater attenuation of morphine tolerance with no alteration of baseline hot plate latency or morphine-induced antinociception was observed when OFQ/N was administered in this area of the rat brain. 5. Taken together, our results demonstrate that OFQ/N may act in the hippocampus to attenuate morphine tolerance.
Insights
Orphanin FQ/nociceptin (OFQ/N) may help reduce morphine tolerance. Studies show OFQ/N administered to the hippocampus attenuated the development of tolerance to morphine
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Opioid receptor-like (ORL-1) receptor studies and orphanin FQ/nociceptin (OFQ/N) antibodies suggest OFQ/N involvement in morphine tolerance.
- Morphine tolerance, a decreased response to morphine's pain-relieving effects, is a significant clinical challenge.
Purpose of the Study:
- To investigate if exogenous OFQ/N administration modulates the development of tolerance to morphine's antinociceptive effects.
- To explore the role of the hippocampus in OFQ/N's modulation of morphine tolerance.
Main Methods:
- Rats received daily saline or morphine injections for 3 days, followed by intracerebroventricular injections of artificial cerebrospinal fluid (aCSF) or OFQ/N.
- OFQ/N dosage increased daily (7.5, 15, 30 nmol).
- Morphine tolerance was assessed on day 4 using a hot plate test.
Main Results:
- Repeated OFQ/N treatment did not affect baseline nociception or morphine-induced antinociception.
- OFQ/N treatment significantly attenuated the development of morphine tolerance.
- Administering OFQ/N specifically to the hippocampus resulted in greater attenuation of morphine tolerance without altering baseline or morphine-induced antinociception.
Conclusions:
- OFQ/N administration attenuates the development of morphine tolerance.
- The hippocampus appears to be a key site where OFQ/N exerts its effect in modulating morphine tolerance.
- These findings suggest OFQ/N as a potential therapeutic target for managing opioid tolerance.