title: Sensitization of enteric neurons to morphine by HIV-1 Tat protein.
abstract: BACKGROUND
  Gastrointestinal (GI) dysfunction is a major cause of morbidity in acquired immunodeficiency syndrome (AIDS). HIV-1-induced neuropathogenesis is significantly enhanced by opiate abuse, which increases proinflammatory chemokine/cytokine release, the production of reactive species, glial reactivity, and neuronal injury in the central nervous system. Despite marked interactions in the gut, little is known about the effects of HIV-1 in combination with opiate use on the enteric nervous system.
  
  
  METHODS
  To explore HIV-opiate interactions in myenteric neurons, the effects of Tat ± morphine (0.03, 0.3, and 3 μM) were examined in isolated neurons from doxycycline- (DOX-) inducible HIV-1 Tat(1-86) transgenic mice or following in vitro Tat 100 nM exposure (>6 h).
  
  
  RESULTS
  Current clamp recordings demonstrated increased neuronal excitability in neurons of inducible Tat(+) mice (Tat+/DOX) compared to control Tat-/DOX mice. In neurons from Tat+/DOX, but not from Tat-/DOX mice, 0.03 μM morphine significantly reduced neuronal excitability, fast transient and late long-lasting sodium currents. There was a significant leftward shift in V(0.5) of inactivation following exposure to 0.03 μM morphine, with a 50% decrease in availability of sodium channels at -100 mV. Similar effects were noted with in vitro Tat exposure in the presence of 0.3 μM morphine. Additionally, GI motility was significantly more sensitive to morphine in Tat(+) mice than Tat(-) mice.
  
  
  CONCLUSIONS
  Overall, these data suggest that the sensitivity of enteric neurons to morphine is enhanced in the presence of Tat. Opiates and HIV-1 may uniquely interact to exacerbate the deleterious effects of HIV-1-infection and opiate exposure on GI function.
authors.affiliation: Departments of Pharmacology & Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fitting
authors.forename: J
authors.initials: J
authors.lastname: Ngwainmbi
authors.forename: M
authors.initials: M
authors.lastname: Kang
authors.forename: F A
authors.initials: FA
authors.lastname: Khan
authors.forename: D L
authors.initials: DL
authors.lastname: Stevens
authors.forename: W L
authors.initials: WL
authors.lastname: Dewey
authors.forename: P E
authors.initials: PE
authors.lastname: Knapp
authors.forename: K F
authors.initials: KF
authors.lastname: Hauser
authors.forename: H I
authors.initials: HI
authors.lastname: Akbarali
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059333:Central Nervous System Sensitization / Q000187:drug effects*; D017615:Enteric Nervous System / Q000187:drug effects* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007082:Ileum / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000633:toxicity*
chemical_list: D017450:Receptors, Opioid, mu; D015222:Sodium Channels; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine
keywords: HIV-1 Tat; MOR-1 expression; enteric neurons; excitability; gut; ileum; opioid drug abuse; sodium currents