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Altered hematopoiesis, behavior, and sexual function in mu opioid receptor-deficient mice
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA.
Abstract:
The mu opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the mu opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.
Insights
The mu opioid receptor, targeted by narcotics like morphine, plays a key role in pain relief. This study reveals its unexpected involvement in regulating the host defense and reproductive systems.
Area of Science:
- Neuroscience
- Pharmacology
- Physiology
Background:
- The mu opioid receptor is the primary target for opioid analgesics like morphine and heroin.
- It mediates key effects of opioids, including pain relief and euphoria.
- The receptor's broader physiological roles beyond pain modulation are not fully understood.
Purpose of the Study:
- To investigate the physiological functions of the mu opioid receptor.
- To explore the receptor's role in motor function, host defense, and reproductive systems.
- To understand the implications of mu opioid receptor disruption in a mouse model.
Main Methods:
- Utilized a mouse model with a genetically disrupted mu opioid receptor gene via homologous recombination.
- Assessed motor function, including locomotor activity, in homozygous and wild-type mice.
- Analyzed hematopoietic progenitor cell proliferation in bone marrow and spleen.
- Evaluated reproductive parameters in male homozygous mice, including mating activity, sperm characteristics, and litter size.
Main Results:
- Mice lacking functional mu opioid receptors exhibited altered motor function and reduced baseline locomotor activity.
- Morphine administration failed to alter locomotor activity in receptor-deficient mice.
- Increased proliferation of hematopoietic progenitor cells was observed in bone marrow and spleen, suggesting a link between the opioid system and hematopoiesis.
- Male mice with disrupted mu opioid receptors showed impaired sexual function, reduced sperm count and motility, and smaller litter sizes.
Conclusions:
- The mu opioid receptor plays a significant role in regulating motor activity.
- A functional mu opioid receptor is unexpectedly involved in the host defense system, specifically in hematopoiesis.
- The mu opioid receptor is crucial for normal reproductive physiology in male mice.
- These findings suggest novel functions for the mu opioid receptor in hematopoiesis and reproduction, extending beyond its established role in analgesia.