Repeated Morphine Exposure Reversibly Impairs Spike Generation and Repetitive Firing in a Functionally Distinct Subpopulation of Orexin Neurons

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.