title: Brain-derived neurotrophic factor modulates antiretroviral-induced mechanical allodynia in the mouse.
abstract: Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of HIV/AIDS treatment to reduce viral load. However, these drugs can induce chronic neuropathic pain, leading to increased morbidity in HIV patients. This study examines the role of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn (SDH) in development of mechanical allodynia in male C57BL/6J mice treated with the NRTI stavudine (d4T). After d4T administration, mice developed increased neuronal activity and BDNF expression in the SDH and hind paw mechanical allodynia that was exacerbated by intrathecal BDNF administration. Intrathecal BDNF alone also increased neuronal activity and caused mechanical allodynia. Because excess BDNF amplified d4T-induced mechanical allodynia and neuronal activity, the impact of decreasing BDNF in the SDH was investigated. After d4T, BDNF heterozygous mice were less allodynic than wild-type littermates, which was negated by intrathecal BDNF administration. Finally, pretreatment with intrathecal trkB-Fc chimera prior to d4T or administration of the tyrosine kinase inhibitor K252a 3 days after d4T blocked BDNF-mediated signaling, significantly attenuated the development of mechanical allodynia (trkB-Fc), and decreased neuronal activity (trkB-Fc and K252a). Taken together, these findings provide evidence that BDNF in the SDH contributes to the development of NRTI-induced painful peripheral neuropathy and may represent a new therapeutic opportunity.
authors.affiliation: Department of Organizational Systems and Adult Health, School of Nursing, University of Maryland, Baltimore, Maryland 21201-1579, USA. renn@son.umaryland.edu
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Renn
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Sherrie
authors.initials: S
authors.lastname: Lessans
authors.forename: Peter
authors.initials: P
authors.lastname: Rhee
authors.forename: W Cameron
authors.initials: WC
authors.lastname: McGuire
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Smith
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Traub
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D018119:Stavudine / Q000633:toxicity*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D020813:Receptor, trkB