Release of β-endorphin and methionine-enkephalin into cerebrospinal fluid during deep brain stimulation for chronic pain

Effects of stimulation locus and site of sampling

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✓ The authors systematically studied the release of the endogenous opioid peptides β-endorphin and methionine (met)-enkephalin into the cerebrospinal fluid (CSF) during deep brain stimulation in patients suffering from otherwise intractable chronic pain. Nine patients were included in the study; six had stimulation electrodes placed in both the periventricular gray matter (PVG) and the thalamic nucleus ventralis posterolateralis (VLP) and three in the PVG only. Immunoreactivity of β-endorphin and met-enkephalin (β-EPir and MEir, respectively) was measured by radioimmunoassays in ventricular and lumbar CSF samples obtained before, during, and after stimulation. Prestimulation concentrations of β-EPir and MEir were lower in ventricular than in lumbar CSF (6.6 ± 0.5 vs. 13.7 ± 1.0 pmol/liter, p = 0.0001, for β-EPir; 33.6 ± 5.1 vs. 48.3 ± 3.2 pmol/liter, p < 0.05, for MEir). Ventricular CSF concentrations of both β-EPir and MEir increased significantly during PVG stimulation, whereas VPL stimulation was without effect. No changes were seen in lumbar CSF levels of the peptides during stimulation in either site. A significant inverse relationship was found between the “during:before stimulation” ratios of visual analog scale ratings and β-EPir levels during PVG stimulation. The β-EPir and MEir concentration during:before stimulation ratios were positively correlated, whereas no correlation was present in prestimulation samples from ventricular or lumbar CSF. High-performance liquid chromatography of ventricular CSF pools obtained during PVG stimulation revealed that major portions of β-EPir and MEir eluted as synthetic β-endorphin and met-enkephalin, respectively, thus documenting the release of β-endorphin and met-enkephalin into ventricular CSF during PVG stimulation. The finding of a direct relationship between β-EPir release and pain alleviation may suggest a role for β-endorphin in the analgesic mechanism of PVG stimulation.

Article Information

Address reprint requests to: Flemming W. Bach, M.D., Anesthesiology Research Laboratory 0818, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0818.

© AANS, except where prohibited by US copyright law.

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Figures

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    Left: Graphs showing concentrations of β-endorphin immunoreactivity (β-EPir, upper) and methionine-enkephalin immunoreactivity (MEir, lower) in ventricular cerebrospinal fluid (CSF) sampled immediately before (Time 0). at 5, 10, and 20 minutes after initiation of periventricular gray matter (PVG) stimulation (horizontal bar), and at 30 minutes after stimulus cessation (Time 50 minutes) in eight patients (pt.'s). The ventricular CSF samples obtained during PVG stimulation were lost for Case 9. Center and Right: Graphs showing concentrations of β-EPir (center) and MEir (right) in ventricular (upper) and lumbar (lower) CSF sampled at 5, 10, and 20 minutes after initiation of PVG stimulation (shaded bars) and at 30 minutes poststimulation (30 min p.s., open bars). The concentrations (means ± standard error of the means) are expressed as percent change from the prestimulation value. * = mean peptide concentrations were significantly different from the prestimulation level according to analysis of variance for repeated measures.

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    Left: Graphs showing concentrations of β-endorphin immunoreactivity (β-EPir, upper) and methionine-enkephalin immunoreactivity (MEir, lower) in ventricular cerebrospinal fluid (CSF) sampled immediately before (Time 0), at 5, 10, and 20 minutes after initiation of thalamic nucleus ventralis posterolateralis (VPL) stimulation (horizontal bar), and at 30 minutes after stimulus cessation (Time 50 minutes) in individual patients (pt.'s). Center and Right: Graphs showing concentrations of β-EPir (center) and MEir (right) in ventricular (upper) and lumbar (lower) CSF sampled at 5, 10, and 20 minutes after initiation of VPL stimulation (shaded bars) and at 30 minutes poststimulation (30 min p.s., open bars). The concentrations (means ± standard error of the means) are expressed as percent change from the prestimulation value.

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    Graphs showing the relationships between β-endorphin immunoreactivity (β-EP), methionineenkephalin immunoreactivity (ME-ir), and visual analog scale (VAS) rating ratios after periventricular gray matter (PVG) stimulation (a, b, and c) and thalamic nucleus ventralis posterolateralis (VPL) stimulation (d, e, and f). The values are expressed as the ratio of the average ventricular cerebrospinal fluid data at 5, 10, and 20 minutes after the initiation of stimulation and the prestimulation value. The numbers attached to the data points refer to the case numbers from Table 1. The linear regression lines are: y = 0.51x + 1.26 (a) and y = 1.99x - 0.95 (c).

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    Graphs showing the high-performance liquid chromatography elution patterns of cerebrospinal fluid (CSF) fractions analyzed for β-endorphin immunoreactivity (ir) (left) and methionine (met)-enkephalinir (right) with C-terminal-directed antiserum before (solid lines) and after (dashed lines). periventricular gray matter stimulation and with N-terminal-directed antiserum after stimulation (dotted line). The acetonitrile gradient is indicated by the dotted and dashed line (right). Identical volumes of oxidized ventricular CSF pools were examined, and the column was calibrated with the following standard peptides: oxidized destyrosine-met-enkephalin (a); oxidized met-enkephalin (b); nonoxidized met-enkephalin (c); oxidized N-acetylated β-endorphin (d); oxidized β-endorphin (e); and oxidized β-endorphin 1–26 (f).

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