Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice.
Opiate abuse reportedly can exaggerate complications of human immunodeficiency virus type-1 (HIV-1) infection in the central nervous system (CNS), while opiate drugs are often indicated in the treatment of HIV-1-related neuropathic pain. Despite this quandary, few studies have assessed the relationship between the duration or extent of HIV-1 infection and the intrinsic neurobehavioral responsiveness to opioids. To address this problem, doxycycline (DOX)-inducible HIV-Tat(1-86) transgenic mice were used as a model for HIV-1-associated neurocognitive disorders, which permitted the regulation of Tat exposure and duration. The effects of continuous Tat induction on the activity of morphine were examined at weekly intervals using standard behavioral assays for nociception and motor function. In the spinal cord, Tat mRNA levels did not increase until the second and third weeks following induction, which corresponded to a significant loss of morphine antinociception as assessed in the tail-flick test. Alternatively, in the striatum, sustained increases in Tat mRNA expression during the second week of induction coincided with significant decreases in rotarod performance and interactions with morphine. Importantly, the behavioral effects of morphine differed depending on the timing and location of Tat expression, with increases in Tat transcript levels in the spinal cord and striatum corresponding to significant alterations in morphine-dependent nociception and rotarod performance, respectively. Assuming Tat levels contribute to the clinical manifestations of HIV-1, the results suggest that regional differences in viral load and opioid phenotype might influence the nature and degree that opiate responsiveness is altered in HIV-1-infected individuals.
Department of Pharmacolog, Virginia Commonwealth University, Richmond, VA 23298, USA. sfitting@vcu.edu
Sylvia
S
Fitting
Krista L
KL
Scoggins
Ruqiang
R
Xu
Seth M
SM
Dever
Pamela E
PE
Knapp
William L
WL
Dewey
Kurt F
KF
Hauser
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015696:Gene Products, tat / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D015696:Gene Products, tat; D009020:Morphine