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Ronald F. Young, Flemming W. Bach, Alan S. Van Norman and Tony L. Yaksh

✓ 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.

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Burton M. Onofrio and Tony L. Yaksh

✓ The present report details the characteristics of the analgesic effects of morphine administered chronically by infusion pumps implanted in 53 patients suffering from terminal metastatic disease. The median postimplant survival time in these patients was 4 months. Patients (mean age 58 years) were characterized according to the duration of pain before pump implantation (mean 16 months), prior consumption of systemic opioids (mean one to six daily analgesic equivalents of morphine), and their response to a trial intrathecal dose of morphine (1 to 2 mg). The median infusion dose at 2 weeks was 3.8 mg/day. The analgesic index, calculated as (quality of pain relief × duration of pain relief in hours)/morphine dose in mg, that was observed after the trial dose of morphine was determined for each patient. A close correlation was observed between the acute (2-week) infusion dose necessary to produce pain relief and the analgesic index such that the infusion dose = −8.0 × log (analgesic index) + 17.1. By 16 weeks, the mean spinal morphine dose for the group had increased by a factor of about 2.5; however, significant variation in the dose incrementation was documented. The maximum increase was observed in patients with a low analgesic index, and this rapid incrementation was usually correlated with an unsatisfactory overall outcome. Evidence that long-term infusion continues to yield analgesia was evidenced in six cases where there was an unanticipated loss of drug infusion and a corresponding increase in parenteral narcotic consumption. These data indicate the long-term efficacy and safety of spinal opioid infusion in patients with terminal cancer, and emphasize the advantage of assessing the sensitivity of the patient to spinal opioids by a standardized trial injection prior to pump placement as a prognostic indication of outcome.

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Max E. Ots, Tony L. Yaksh, Robert E. Anderson and Thoralf M. Sundt Jr.

✓ Nimodipine, a dihydropyridine that interacts with a Ca++ channel-associated binding site, when delivered (30 to 150 µg/kg) intra-arterially (ia) to enflurane-anesthetized cats, produced a dose-dependent suppression of seizures evoked by pentylenetetrazol. A comparable suppression was produced by clonazepam (1 to 30 µg/kg, ia). Phenytoin was maximally effective only at nearly lethal doses (90 mg/kg, ia). Verapamil, a diphenyl-alkylamine that interacts with a separate Ca++ channel-associated site, at the maximum nonlethal dose (6 mg/kg, ia) resulted in a mild facilitation of seizure activity. The drug vehicle used in these studies (50% polyethylene glycol-400) had no effect when given alone. Regional cerebral blood flow (rCBF) as measured by the clearance of xenon-133 was markedly elevated immediately after the onset of seizure activity (89 ± 3 to 168 ± 4 ml/100 gm/min). Concurrent with their resolution of the seizure activity, both nimodipine and clonazepam reduced rCBF to near preseizure levels and preserved the rCBF response to hypercarbia which would otherwise have been abolished following prolonged seizure activity. Moreover, the effect of nimodipine on rCBF and seizures occurred without any prominent alterations in mean arterial blood pressure as compared to preseizure levels. These data support the proposition that a dihydropyridine Ca++ channel binding site may play a role in modulating paroxysmal neuronal activity, and suggest that this class of agents may reflect a novel group of antiepileptic drugs.

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Tony L. Yaksh

✓ A review of the spinal organization of opioid receptor systems and endorphins is presented. The review is a consideration of the physiological mechanisms underlying the effect of spinal opioids, the pharmacology of the opioid receptors that moderate a variety of spinal processing systems, and the endorphin systems that act upon the spinal receptors.

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Treatment of experimental focal cerebral ischemia with mannitol

Assessment by intracellular brain pH, cortical blood flow, and electroencephalography

Fredric B. Meyer, Robert E. Anderson, Thoralf M. Sundt Jr. and Tony L. Yaksh

✓ Intracellular brain pH, cortical blood flow (CBF), and electrocorticograms were recorded in regions of severe and moderate ischemia in 10 control rabbits and 10 rabbits given mannitol, 1 gm/kg, after occlusion of a major branch of the middle cerebral artery. Pooling the data from all 20 animals, preocclusion CBF was 46.4 ±3.6 ml/100 gm/min and intracellular brain pH was 7.01 ± 0.04 (means ± standard error of the means). Although mannitol administration mildly improved CBF in regions of severe ischemia, this increase was not sufficient to prevent metabolic deterioration as assessed by brain pH. However, in regions of moderate ischemia, CBF improved significantly with mannitol and the gradual decline in brain pH observed in control animals was prevented. For example, in the treated moderate ischemia sites 4-hour postocclusion CBF and pH values were 31.8 ml/100 gm/min and 6.89 ± 0.09, respectively, as compared to control values of 14.3 ml/ 100 gm/min and 6.75 ± 0.06. These results suggest that mannitol may be of benefit in stabilizing regions of moderate, but not severe, ischemia after vessel occlusion.

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Fredric B. Meyer, Robert E. Anderson, Tony L. Yaksh and Thoralf M. Sundt Jr.

✓ Intracellular brain pH, cortical blood flow, and electroencephalograms (EEG's) were recorded in severely and moderately ischemic regions in 10 control and 10 nimodipine-treated rabbits prior to and following major branch occlusion of the middle cerebral artery (MCA). Preocclusion cortical blood flow was 51 ml/100 gm/min and intracellular brain pH was 7.01 in both the control and the treated animals. After MCA occlusion, the severely ischemic regions in the control group showed initial and 4-hour postocclusion flows of 12.7 and 5.2 ml/100 gm/min with a brain pH of 6.64 and 6.08, respectively. In animals given nimodipine after MCA occlusion, blood flow increased from 10.5 to 18.8 ml/100 gm/min, with an associated elevation in intracellular brain pH from 6.57 to 6.91. Comparable findings were observed in areas of moderate ischemia. Improvements in cortical blood flow, intracellular brain pH, and EEG attenuations produced by nimodipine were all statistically significant. Inspection of the cortex revealed reversal of cortical pallor and small-vessel spasm following treatment with nimodipine. It is hypothesized that nimodipine exerts its effects through reversal of ischemia-induced secondary vasoconstriction, and that this drug may be an important adjunctive treatment for patients with focal cerebral ischemia.

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Tomoo Furui, Kyoko Satoh, Yoshio Asano, Sadashi Shimosawa, Michiaki Hasuo and Tony L. Yaksh

β-Endorphin was measured in cerebrospinal fluid (CSF) and plasma in patients with cerebral infarction at acute (4 to 48 hours) and chronic (1 month) stages. Only CSF samples obtained in the acute stage showed β-endorphin values that were statistically higher than those measured in a control population. This finding suggests that infarction at its acute stage gives rise to an increased release of β-endorphin. Such a mechanism is consistent with the possibility that the reported therapeutic effect of naloxone in cerebral ischemic lesions may result in part from the antagonism of the centrally released endorphin, β-endorphin.