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Repeated Morphine Exposure Reversibly Impairs Spike Generation and Repetitive Firing in a Functionally Distinct
Elizabeth A Berry1, Ellen N Huhulea1, Masaru Ishibashi2
1Department of Physiology, New York Medical College, Valhalla, New York 10595.
Abstract:
Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Postmortem brains from opioid users and opioid-treated rodents have orexin somata that become ∼20% smaller and ∼50% more numerous and are postulated to promote hypermotivation for drug seeking though increased orexin release. Biophysical considerations suggest that the decreased soma size should increase cellular excitability; however, the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated for 2 weeks by daily morphine or saline injections. Paradoxically, we found that while daily morphine decreased the average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as "H-type" while entirely sparing "D-type" neurons. This impairment was manifest by smaller, broader action potentials, variable firing, and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after 4 weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence.
Insights
Chronic morphine exposure impairs orexin neuron excitability, particularly in H-type neurons, affecting drug dependence. This suggests altered orexin peptide release in opioid addiction.
Area of Science:
- Neuroscience
- Neuropharmacology
- Cellular Electrophysiology
Background:
- Orexin (hypocretin) neuropeptides are crucial for regulating sleep-wake cycles and reward processing.
- Orexin neurons respond to drug cues and undergo structural changes with chronic drug use, potentially influencing addiction.
- Opioid dependence is associated with altered orexin neuron morphology, but the impact on neuronal firing and peptide release remains unclear.
Purpose of the Study:
- To investigate the effects of chronic morphine exposure on the intrinsic electrophysiological properties of orexin neurons.
- To determine if chronic opioid treatment alters the excitability and firing patterns of orexin neurons.
- To explore the differential impact of morphine on distinct orexin neuron subpopulations.
Main Methods:
- Whole-cell electrophysiological recordings were performed on orexin-EGFP neurons from male mice.
- Mice were treated daily with morphine or saline for two weeks.
- Intrinsic electrophysiological properties, including action potential characteristics and firing gain, were assessed.
Main Results:
- Daily morphine treatment reduced orexin neuron soma size but paradoxically impaired excitability in a subpopulation of "H-type" neurons.
- "D-type" orexin neurons were unaffected by morphine treatment.
- Impaired excitability included smaller, broader action potentials, variable firing, and reduced firing gain, which normalized after four weeks of withdrawal.
Conclusions:
- Chronic morphine exposure differentially affects orexin neuron subtypes, impairing the excitability of H-type neurons.
- These electrophysiological changes suggest an impaired capacity for synaptic input encoding and neuropeptide release in H-type orexin neurons during opioid dependence.
- The findings provide insights into the neurobiological mechanisms underlying opioid addiction and dependence.
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