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The Journal of Neuroscience, June 15, 2001, 21(12):4469-4477
Brain-Derived Neurotrophic Factor Is Released in the Dorsal Horn
by Distinctive Patterns of Afferent Fiber Stimulation
Isobel J.
Lever1,
Elizabeth J.
Bradbury1,
Joanna R.
Cunningham2,
David W.
Adelson3,
Martyn
G.
Jones1,
Stephen B.
McMahon1,
Juan Carlos G.
Marvizón3, and
Marzia
Malcangio1
1 Neuroscience Research Center and
2 Department of Pharmacology, Guy's, King's, and St.
Thomas' School of Biomedical Sciences, King's College London, London
SE1 1UL, United Kingdom, and 3 CURE: Digestive Diseases
Research Center, Neuroenteric Disease Program, Department of Medicine,
University of California, Los Angeles, California 90073
Brain-derived neurotrophic factor (BDNF) is synthesized by small
neuron cell bodies in the dorsal root ganglia (DRG) and is anterogradely transported to primary afferent terminals in the dorsal
horn where it is involved in the modulation of painful stimuli. Here we
show that BDNF is released in the rat isolated dorsal horn after
chemical stimulation by capsaicin or electrical stimulation of dorsal
roots. Capsaicin superfusion (1-100 µM) induced a
dose-dependent release of BDNF, measured using ELISA. The highest dose
of capsaicin also induced a depletion of BDNF protein in the dorsal
horn. BDNF release was also seen after electrical stimulation of the
dorsal roots at C-fiber strength. This release was encoded by specific
patterns of afferent fiber stimulation. Neither continuous
low-frequency (480 pulses, 1 Hz) nor tetanic high-frequency (300 pulses
in 3 trains, 100 Hz) stimulation evoked release of BDNF, although
substance P (SP) release was observed under both of these conditions.
However, BDNF was released after short bursts of high-frequency
stimulation (300 pulses in 75 trains, 100 Hz) along with SP and
glutamate. The NMDA antagonist D-AP-5 inhibited
electrically evoked BDNF release. BDNF release was also measured after
systemic or intrathecal NGF treatment. This upregulated BDNF content in
the DRG and increased the capsaicin-evoked release of BDNF. Similarly,
the amount of BDNF released by burst stimulation was increased after
NGF treatment. This activity-dependent release continued to be encoded
solely by this stimulation pattern. These experiments demonstrate that
BDNF release in the dorsal horn is encoded by specific patterns of
afferent fiber stimulation and is mediated by NMDA receptor activation.
Key words:
neurotrophin release; sensory neurons; capsaicin; burst
stimulation; NMDA receptor; nociception
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124469-09$05.00/0
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