title: Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice.
abstract: Despite considerable evidence that chronic opiate use selectively affects the pathophysiologic consequences of human immunodeficiency virus type 1 (HIV-1) infection in the nervous system, few studies have examined whether neuro-acquired immune deficiency syndrome (neuroAIDS) might intrinsically alter the pharmacologic responses to chronic opiate exposure. This is an important matter because HIV-1 and opiate abuse are interrelated epidemics, and HIV-1 patients are often prescribed opiates as a treatment of HIV-1-related neuropathic pain. Tolerance and physical dependence are inevitable consequences of frequent and repeated administration of morphine. In the present study, mice expressing HIV-1 Tat in a doxycycline (DOX)-inducible manner [Tat(+)], their Tat(-) controls, and control C57BL/6 mice were chronically exposed to placebo or 75-mg morphine pellets to explore the effects of Tat induction on morphine tolerance and dependence. Antinociceptive tolerance and locomotor activity tolerance were assessed using tail-flick and locomotor activity assays, respectively, and physical dependence was measured with the platform-jumping assay and recording of other withdrawal signs. We found that Tat(+) mice treated with DOX [Tat(+)/DOX] developed an increased tolerance in the tail-flick assay compared with control Tat(-)/DOX and/or C57/DOX mice. Equivalent tolerance was developed in all mice when assessed by locomotor activity. Further, Tat(+)/DOX mice expressed reduced levels of physical dependence to chronic morphine exposure after a 1-mg/kg naloxone challenge compared with control Tat(-)/DOX and/or C57/DOX mice. Assuming the results seen in Tat transgenic mice can be generalized to neuroAIDS, our findings suggest that HIV-1-infected individuals may display heightened analgesic tolerance to similar doses of opiates compared with uninfected individuals and show fewer symptoms of physical dependence.
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia sfitting@email.unc.edu kurt.hauser@vcuhealth.org.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Fayez A
authors.initials: FA
authors.lastname: Khan
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Scoggins
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Enga
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: Department of Pharmacology and Toxicology (S.F., D.L.S., F.A.K., K.L.S., R.M.E., P.M.B., P.E.K., W.L.D., K.F.H.), Department of Anatomy and Neurobiology (P.E.K., K.F.H.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia sfitting@email.unc.edu kurt.hauser@vcuhealth.org.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D004361:Drug Tolerance / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000235:genetics* / Q000523:psychology*; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D009437:Neuralgia / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000523:psychology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D009294:Narcotics; D054322:tat Gene Products, Human Immunodeficiency Virus; D009020:Morphine; D004318:Doxycycline