Yoshio Hosobuchi

Headache may arise from perturbation of brain

SYNOPSIS

NALOXONE REVERSAL OF ISCHAEMIC NEUROLOGICAL DEFICITS IN MAN

Abstract Two patients with cerebral ischaemia and one patient with cerebral infarction received intravenous infusions of the opiate antagonist naloxone or saline in double-blind manner. Naloxone completely reversed neurological deficits in both patients with cerebral ischaemia, but did not in the patient with cerebral infarction. Naloxone administration produced no changes in blood pressure, pulse rate, respiratory rate, temperature, or arterial blood gases. Intravenous administration of morphine sulphate profoundly exacerbated hemiparesis in one patient without alteration of vital signs; hemiparesis was completely reversed by naloxone.

Electrical Stimulation of the Cervical Spinal Cord Increases Cerebral Blood Flow in Humans

Ten patients were studied to determine the effect of spinal cord stimulation on CBF. In 5 patients using a cervical spinal cord stimulator, the stimulation produced a significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia. Thoracic cord stimulation, used by the other 5 patients, had no effect on CBF. Atropine had no effect on the alteration in CBF produced by cervical cord stimulation. Indomethacin, however, partially blocked the effect. These heuristic observations may have implications for the future treatment of cerebrovascular insufficiency in humans.

The majority of unmyelinated afferent axons in human ventral roots probably conduct pain

&NA; Three patients with intractable chest pain had undergone dorsal rhizotomy. None had obtained relief, but all three had developed dysesthesia and hyperesthesia, in addition to the original pain persisting in the supposedly deafferented area. Dorsal ganglionectomy was performed for these 3 patients in 1976 and they were followed for 3 years. Following ganglionectomy two of the three developed total anesthesia, including loss of dysesthesia, hyperesthesia, and the original pain. Light and electron microscopical examination of the ventral roots removed at the time of ganglionectomy showed that unmyelinated axons constituted approximately 25% of the total fiber count. Two ventral roots from one patient who previously had serendipitous removal of dorsal ganglia showed a marked reduction in the population of unmyelinated axons. The observations support Coggeshalls contention that the majority of unmyelinated axons in the ventral roots are sensory and probably conduct pain.

Autopsy analysis of the safety, efficacy and cartography of electrical stimulation of the central gray in humans

Electrical brain stimulation is effective in controlling certain intractable chronic pain syndromes in humans, but the specific target site(s) for stimulation producing a maximal analgesic effect is (are) not well defined. This prospective study correlates the clinical results of chronic stimulation of the periaqueductal gray (PAG) and periventricular gray (PVG) matter in humans with the anatomic site of electrode placement as determined at autopsy, and documents the histologic reactions to electrode implantation and electrical stimulation of the area. Seven patients underwent electrode implantation to control their chronic pain; two had electrodes implanted bilaterally. All patients obtained complete analgesia with stimulation, although 3 subsequently found the stimulation to have diminished efficacy. The opiate antagonist naloxone reversed the analgesia in the 4 patients so tested. All 7 patients later died of causes unrelated to electrode implantation or stimulation. Postmortem analysis showed that, for 6 of the 9 electrodes implanted, the electrode tip was located in the ventrolateral PAG at the level of the posterior commissure; the other 3 electrodes were found in the white matter adjacent to the PAG. No evidence of gliosis or parenchymal reaction was observed along the tracts and tips of the electrodes. The results indicate that the ventrolateral PAG and PVG matter at the level of the posterior commissure is the optimal site for therapeutic electrical brain stimulation for opiate-responsive pain in humans.

The Current Status of Analgesic Brain Stimulation

This paper reviews the authors nine years of experience in analgesic brain stimulation. During this time, of 22 patients with pain of peripheral origin who were treated with periaqueductal gray (PAG), stimulation 16 achieved successful control of pain. Of 40 patients who presented with deafferentation pain, 16 were able to control their dysesthesia by brain stimulation of the subcortical somatosensory region alone; follow-up was over a long period. The mechanism of deafferentation pain is poorly understood and the effectiveness of subcortical somatosensory electrical stimulation to relieve such pain is based on empirical observation. The analgesia produced by PAG stimulation appears to be mediated by the release of beta-endorphin from the anterior hypothalamus. The released beta-endorphin binds to the opiate receptors in the PAG and activates the descending pain-inhibitory pathway. However, the repetitive stimulation of this serotonergic system produces tolerance to its analgesic effect, due to a decreased rate of serotonin turnover. Loading of the serotonin precursor by dietary supplementation of the essential amino acid L-tryptophan reverses this tolerance.

Naloxone reversal and morphine exacerbation of neurologic deficits secondary to focal cerebral ischemia in baboons

The effects of an opiate agonist (morphine) and antagonist (naloxone) on neurologic function in conditions of acute and subacute focal cerebral ischemia were tested in a baboon model. Fourteen baboons (Papio papio) underwent unilateral transorbital microsurgical occlusion of the middle cerebral artery (MCA). Blood pressure, heart rate and core temperature were monitored continuously; frequent arterial blood gas measurements were made. Cardiac output, cardiac filling pressures, and regional cerebral blood cross-flow were measured in selected baboons. Naloxone administered intravenously consistently reversed hemiparesis and hemiplegia in all baboons for as long as they lived (4 h to 8 days postocclusion). Morphine administered intravenously converted hemiparesis to hemiplegia; this effect was naloxone-reversible. There were no significant changes in any parameter measured after the administration of either drug. Phenylephrine (used to elevate mean arterial pressure to 20 mm higher than the highest pressure measured after naloxone administration) and isoproterenol (used to elevate cardiac output to 1 l/min higher than the highest value measured after naloxone administration) produced no change in neurologic function. It appears that naloxone can reverse, and morphine exacerbate, focal ischemic neurologic deficits produced in baboons by MCA occlusion. The observed changes in neurologic function are not associated with or mediated by alterations in core temperature or cardiopulmonary functions.

Treatment of Cerebral Ischemia with Electrical Stimulation of the Cervical Spinal Cord

We observed an increase in cerebral blood flow (CBF) for control of pain but were otherwise normal. Based on (hat observation, we implanted stimulators for cervical spinal cord stimulation (cSCS) in three patients who had symptomatic cerebral ischemia. Two had severe basivertebral occlusive disease and one had bilateral carotid occlusive disease. In all three cases, cSCS alleviated the symptoms of ischemia. Xenon‐CBF studies or single‐photon emission computer tomography (SPECT) showed increased CBF in response to cSCS. Although no mechanism clearly responsible for this remarkable therapeutic efficacy can be proposed yet, further clinical trials of cSCS for inoperable cerebral ischemia may be justified.

Effect of naloxone on neurologic deficit and cortical blood flow during focal cerebral ischemia in cats

Using middle cerebral artery occlusion in the cat as a model of focal cerebral ischemia, we investigated the effect of naloxone on both neurologic deficit and regional cortical blood flow during cerebral ischemia. In all animals with major strokes, 2 mg/ml naloxone administered intravenously produced a dramatic reversal of neurologic symptoms four hours after the ischemic lesion. Animals were then anesthetized and cortical blood flow was measured by the hydrogen clearance method. Blood flow in the ischemic cortex was noted to be approximately 55% that of the control side. Naloxone produced a significant decrease of approximately 20% in cortical blood flow in the ischemic hemisphere while no effect on blood flow on the control side was noted. Thus, naloxone appears to reverse the neurologic deficits following middle cerebral artery occlusion in the cat. This effect appears to be accompanied by a decrease in local blood flow to the ischemic cortex.

Naloxone reversal of ischemic neurologic deficits in baboons is not mediated by systemic effects

Abstract A primate model was used to test the effects of opiate agonists and antagonists on neurologic function in conditions of acute and subacute cerebral ischemia. Fourteen baboons (Papio papio) underwent unilateral transorbital microsurgical occlusion of the middle cerebral artery. Blood pressure, heart rate, and core temperature were monitored continuously, and frequent arterial blood gas measurements were made. In selected baboons, cardiac output, cardiac filling pressures, and regional cerebral blood flow were also measured. Naloxone, administered intravenously, consistently reversed hemiparesis and hemiplegia for a period of 30 minutes in all baboons tested. The animals were tested over a period ranging from 4 hours to 8 days after occlusion. Morphine, administered intravenously to the hemiparetic baboons, rendered them totally hemiplegic; this effect also was reversed with naloxone. There were no significant changes in heart rate, blood pressure, core temperature, or arterial blood gas values after the administration of naloxone or morphine. Elevation of the mean arterial pressure with phenylephrine did not alter hemiplegia, despite elevation of the mean arterial pressure to a level 20 mm higher than the pressure measured after naloxone administration. Cardiac catherization studies showed no significant change in cardiac filling pressures or cardiac output after naloxone or morphine was administered. Isoproterenol, used to elevate cardiac output to 1 liter/min higher than the highest level measured after naloxone administration, produced no change in neurologic function. Regional cortical blood flow in the ischemic hemisphere did not change after naloxone administration. These studies indicate that naloxone can reverse, and morphine can exacerbate, focal ischemic neurologic deficit produced in baboons by contralateral occlusion of the middle cerebral artery. The observed change in neurologic function was not associated with or mediated by alterations in core temperature or cardiopulmonary function.