Ivar Øye

Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia.

&NA; The effect of continuous subcutaneous (s.c.) infusion of ketamine on nerve injury pain was examined in patients with post‐herpetic neuralgia. Five patients that reported pain relief after acute intravenous injection of ketamine were included in this open prospective study. Ketamine was administered continuously in increasing doses using a portable infusion pump (CADD‐PLUS, Pharmacia), and the treatment period for each infusion rate (0.05, 0.075, 0.10, or 0.15 mg/kg/h) was 7 days and nights. Relief Of continuous pain, as evaluated daily by visual analogue scales, was observed at the infusion rate of 0.05 mg/kg/h, but was most marked during infusion of 0.15 mg/kg/h. All the patients reported that ketamine reduced the severity of continuous pain as well as reduced the severity and number of attacks of spontaneous pain. Changes in evoked pain (allodynia and wind‐up‐like pain) were recorded before change of infusion rate. Allodynia was maximally reduced 59–100% after 1 week infusion of 0.05 mg/kg/h, and wind‐up‐like pain was maximally reduced 60–100% after 1 week infusion of 0.15 mg/kg/h. Itching and painful indurations at the injection site was the most bothersome side‐effect and for this reason 1 patient discontinued treatment after 2 weeks. Other common side‐effects were nausea, fatigue and dizziness. The present results show that continuous, spontaneous and evoked pain in patients with post‐herpetic neuralgia is reduced by continuous s.c. infusion of ketamine, but is associated with intolerable side effects.

Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)

Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.

Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain

&NA; We examined the analgesic effect of racemic ketamine and its 2 enantiomers in 16 female patients (age: 20–29 years) suffering acute pain after oral surgery and in 7 female patients (age: 42–79 years) suffering chronic neuropathic orofacial pain. All 3 forms of ketamine consistently relieved postoperative pain, (S)‐ketamine being 4 times more potent than (R)‐ketamine. The analgesic effect was maximal 5 min after i.m. injection and lasted for about 30 min. The 7 patients with neuropathic pain received ketamine at one or several occasions. Four patients (age: 54–79 years) who had suffered pain for more than 5 years did not experience an analgesic effect, whereas 3 patients (age: 42–53 years) who had suffered pain for less than 3 years reported pain relief lasting from 24 h to 3 days. The individual type of response did not depend on the form of ketamine used. The mental side effects were qualitatively similar for the 3 forms of ketamine. Relative to the analgesic effect (S)‐ketamine caused more disturbing side effects than did (R)‐ketamine. The mean serum concentration of each form of ketamine at the time of maximal effect was close to the approximate Kd value for PCP site occupancy by that particular form. This is in concert with the hypothesis that the effect of ketamine on acute nociceptive pain is due to N‐methyl‐D‐aspartate (NMDA) receptor inhibition and adds to the evidence that NMDA receptors are important for the perception of acute, nociceptive pain in humans. The lack of analgesic effect of ketamine in patients who had suffered neuropathic pain for several years shows that NMDA receptors are not involved in the perception of all types of pain and indicates that NMDA receptors become less important for pain perception in older patients with a long pain history. The atypical (prolonged) analgesic effect of ketamine in patients who had suffered neuropathic pain for less than 3 years may be a placebo effect, but the possibility that this effect reflects a permissive role of NMDA receptors during the development of neuropathic pain cannot be excluded.

Evidence of a role for NMDA receptors in pain perception

Both chiral forms of ketamine caused analgesia when administered in subanesthetic doses to human volunteers suffering acute, experimentally induced ischemic pain. S-Ketamine was 4 times more potent than R-ketamine as an analgesic agent in this model system. The relative order of analgesic potency of the two enantiomers was compared to their relative affinity for phencyclidine (PCP) binding sites (associated with the NMDA receptor-operated ion channel) and for sigma binding sites (which are not associated with the NMDA receptor complex). The relative analgesic potency of the enantiomers correlated positively with their relative affinity for PCP sites and negatively with their relative affinity for sigma sites. The results strongly indicate that PCP sites, but not sigma sites, are functional receptors mediating the analgesic effect of ketamine. This is consistent with the hypothesis that NMDA receptors are essential for pain perception in humans. Disturbances of other sensory modalities, in particular somatosensory perception, vision and hearing, were the main side-effects observed. These effects were qualitatively similar for both enantiomers and were closely associated with their analgesic action. The NMDA type of excitatory amino acid receptor thus appears to be widely involved in the processing of sensory afferent signals in the human brain.

Comparison of ketamine and pethidine in experimental and postoperative pain

&NA; The analgesic efficiency of ketamine and pethidine was compared in experimental ischemic pain and postoperative pain after oral surgery. Naloxone 1.6 mg or placebo was given 5 min before the analgesic drug. The subjects recorded their pain on a visual analogue scale. Both ketamine 0.3 mg/kg and pethidine 0.7 mg/kg were effective as analgesics against the two types of pain studied. Naloxone prevented the analgesic effect of pethidine, but had no effect on ketamine analgesia. The results are in accordance with the hypothesis that the analgesic effect of ketamine is mediated by a non‐opioid mechanism, possibly involving PCP‐receptor‐mediated blockade of the NMDA‐receptor‐operated ion channel.

Central nervous system effects of subdissociative doses of (S)‐ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)‐ketamine were measured in a randomized, double‐blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)‐[N‐methyl‐11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N‐methyl‐D‐aspartate receptor complexes. A significant and dose‐dependent reduction of binding was measured as a result of displacement of (S)‐[N‐methyl‐11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)‐ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)‐ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)‐ketamine, measured with positron emission tomography, can be related directly to drug effects.

NMDA‐Receptor Activity Visualized with (S)‐[N‐Methyl‐11C]Ketamine and Positron Emission Tomography in Patients with Medial Temporal Lobe Epilepsy

Summary: Purpose: To determine whether neurochemical activation of the N‐methyl‐D‐aspartate (NMDA) receptor‐gated ion channel shows quantitative changes, measured as binding of 11C‐labeled (S)‐[N‐methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE).

Development of cyclic AMP metabolism in rat liver a correlative study of tissue levels of cyclic AMP, accumulation of cyclic AMP in slices, adenylate cyclase activity and cyclic nucleotide phosphodiesterase activity

Abstract Developmental alterations in the levels of cyclic AMP, adenylate cyclase activity, phosphodiesterase activity and accumulation of cyclic AMP in slices during incubation in vitro were studied in male rat liver. 1. 1. At 1 week before birth adenylate cyclase activity was present. At this stage the enzyme was activated by fluoride, but not by adrenalin or glucagon. At 2 days before birth both adrenalin and glucagon stimulated the adenylate cyclase. 2. 2. During the perinatal period the tissue levels of cyclic AMP, the adenylate cyclase activity and the production of cyclic AMP in slices increased rapidly, reaching maximal values towards the end of the first postnatal week. This peak coincided with a maximal phosphodiesterase activity, indicating an increased cyclic AMP turnover in neonatal liver. 3. 3. When the animals grew older the tissue levels and the rate of synthesis and breakdown of cyclic AMP declined. In addition, the response to adrenalin and glucagon developed differently with increasing age: the stimulatory effect of adrenalin on adenylate cyclase activity and cyclic AMP formation in slices gradually disappeared, whereas response to glucagon persisted.

Effects of dibenzepine and imipramine on the isolated rat heart

Abstract The tricyclic antidepressants, imipramine and dibenzapine and the local anaesthetic drug lidocaine were added to the recirculating perfusate in a rat heart perfusion apparatus. Each drug produced the following effects: (a) A dose-dependent decrease in impulse generation and impulse conduction velocity. (b) A dose-dependent decrease in cardiac contractile force. (c) A dose-dependent decrease in coronary flow preceded by an increase at lower concentrations. (d) A dose-dependent decrease in potassium loss from the heart. (e) Potentiation of the imipramine-induced decrease in contractile force and coronary flow in the presence of lidocaine. Further, in the concentration range in wich the antidepressants produced their cardiac effects, they stabilized eryhrocytes against hypotonic lysis. The antidepressants and the local anaesthetic share this effect and the cardiac effects with a variety of drugs commonly referred to as membrane stabilizers. It is concluded that the membrane stabilizers probably change the properties of biomembranes in a common way, and that the cardiac effects are secondary to these changes.

Cyclic AMP formation and morphology of myocardial cells isolated from adult heart: Effect of Ca2+ and Mg2+

Adult rat heart cells were isolated by perfusion with a calcium-free phosphate buffer containing collagenase. Optimal conditions gave a high proportion of elongated cells. Isoprenaline increased cydic AMP content linearly, with ED50 (dose effective in 50% of the population) about 10(-7) M. Ca2+ made the cells spherical, and it nearly abolished cyclic AMP response as did lack of Mg2+.