Tadanobu Mizuguchi

The Effects of Morphine, MK-801, an NMDA Antagonist, and CP-96,345, an NK1 Antagonist, on the Hyperesthesia Evoked by Carageenan Injection in the Rat Paw

BackgroundThe spinal mechanisms underlying the hyper-esthetic state during inflammation are little understood. To gain a better understanding of these mechanisms, this study evaluated the effects of intrathecal morphine; MK-801, an N-methyl-D aspartic (NMDA) antagonist; and CP-96,345, an NK1 antagonist, on the hyperesthesia observed after carageenan injection of the rat paw. MethodsIn rats injected with 2 mg carageenan, the paw withdrawal latency (PWL) for the injected paw was typically 5–6 s less than that for the untreated paw, at 2 h after the carageenan injection. Drugs were administered 2 h after the carageenan injection. The magnitude of hyperesthesia was evaluated with the difference score (OS), which was calculated by subtracting the PWL of the untreated paw from the PWL of the injected paw. ResultsIntrathecal morphine increased PWLs of both the injected and the untreated paws equally in a dose-dependent manner, but intrathecal morphine did not affect the level of DS. Intrathecal MK-801 increased PWLs of the injected paw to the level of the untreated paw in a dose-dependent manner and increased the DS levels. Intrathecal CP-96,345 had no effect on PWLs of either the injected or the untreated paw. Coad-ministration of MK-801 with morphine reduced the DS for each dose of morphine. ConclusionsThese data indicate that (1) an NMDA receptor, but not an NK1 receptor, plays an important role in maintaining the hyperesthesia after carageenan injection; and (2) NMDA antagonism has a simple additive interaction with morphine in the carageenan model of inflammatory hyperesthesia.

Effects of partial paralysis on the swallowing reflex in conscious humans

The ability to swallow may be affected by administration of a small dose of muscle relaxant. To test the hypothesis that a subparalyzing dose of a muscle relaxant can impair swallowing, effects of partial paralysis produced by pancuronium on the swallowing reflex were investigated in eight conscious subjects. The swallowing reflex was induced by a bolus injection or a continuous infusion of distilled water into the mesopharynx. The swallowing function was assessed by electromyogram of suprahyoid muscles (EMGSH), mesopharyngeal pressure (Pmeso), and hypopharyngeal pressure (Phypo). Peripheral muscle activity was simultaneously determined by train of four ratio (TOFR) of hypothenar muscles to electrical stimulation of ulnar nerve and by hand grip strength (HGS). Following control measurements, measurements during partial paralysis and after recovery from partial paralysis were performed after intravenous administration of pancuronium 0.02 mg/kg. Partial paralysis significantly depressed EMGSH (bolus injection 44.1 +/- 10.0%, continuous infusion 55.9 +/- 10.2% of control value, P less than 0.01). Pmeso also significantly decreased (bolus injection 64.9 +/- 6.7 to 47.8 +/- 5.8 mmHg, P less than 0.01; continuous infusion 63.4 +/- 7.7 to 52.5 +/- 5.8 mmHg, P less than 0.05). The TOFR of peripheral muscles decreased to 81.4 +/- 6.7% of control value (P less than 0.01), and HGS was reduced from 44.6 +/- 1.9 to 39.4 +/- 2.0 kg (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Sevoflurane on Diaphragmatic Contractility in Dogs

The effect of sevoflurane on diaphragmatic contractility was investigated in 12 anesthetized, mechanically ventilated dogs with the thorax opened. Animals were divided into two groups of six each: the sevoflurane and time control groups. We assessed contractility by the transdiaphragmatic pressure (Pdi) during supramaximal stimulation of the phrenic nerve at frequencies of 0.5, 10, 20, 50, and 100 Hz under quasiisometric conditions. The integrated electrical activity (Edi) of the crural and costal parts of the diaphragm (Edi cru, Edi cost) was also measured. In the sevoflurane group, diaphragmatic contractility was determined during three levels of anesthesia, specifically 0, 1.0, and 1.5 minimum alveolar anesthetic concentration (MAC). Measurements were made at the start of the stimulation (initial) and at the end of the 2-s period (2-s). Increasing the depth of sevoflurane anesthesia did not cause any significant differences in Pdi and Edi at 0.5-, lo-, and 20-Hz stimulation. By contrast, at 50- and 100-Hz stimulation, initial Pdi during 1.0 and 1.5 MAC sevoflurane exposure decreased significantly compared with the 0 MAC value (P < 0.05). In addition, there was a statistical difference in 2-s Pdi between 1.0 and 1.5 MAC at 100-Hz stimulation (P < 0.05). The Edi cru showed similar changes in Pdi at both measurements, whereas there was no remarkable change in Edi cost. There was no significant change either in Pdi or in Edi with respect to time in the time control group. We conclude from these results that sevoflurane impairs diaphragmatic contractility through its inhibitory effect on neuromuscular transmission, predominantly of the crural part.

Role of the injury discharge in the development of thermal hyperesthesia after sciatic nerve constriction injury in the rat

BackgroundUsually, a barrage of impulses (“injury discharge”) is evoked following sensory nerve damage. It has been suggested that injury discharge may produce the hyperexcitatory state in the spinal cord, and this hyperexicitability may cause neurogenic pain. In the present study, the authors examined the role of injury discharge in developing the hyperesthetic state following nerve constriction injury. MethodsA model of thermal hyperesthesia caused by a constriction injury created by making four loose ligations around the rat sciatic nerve was examined. To block the injury disharge, 0.5% bupivacaine was applied to the sciati nerve before constriction injury. To block the hyperexcitatory state, (+)-MK-801, an N-methyl-D-aspartate antagonist, was administered intrathecally 15 min before the nerve lesion. Results:Blocking injury discharge significantly delayed the development of hyperesthesia. Bupivacaine had no effect on the development of hyperesthasia when bupivacaine was applied to the sciatic nerve 15 min after the nerve constriction injury. Systemic bupivacaine had no effect on the development of thermal hyperesthesia. Intrathecal (+)-MK-801 also delayed the development of hyperesthesia when (+)-MK-801 was administered intrathecally 15 min before the nerve injury. When (+)-MK-801 was administered 15 min before the nerve injury, (+)-MK-(801) had no effect on the development of hyperesthesia. Conclusion:These results suggest that injury discharge may induce facilitation of spinal dorsal horn neurons, and this spinal facilition may play an important role in developing thermal hyperesthesia following sciatic nerve constriction injury.

Effect of repeated irradiation of low-power He-Ne laser in pain relief from postherpetic neuralgia

In order to investigate the efficacy of repeated irradiation of low-power helium-neon laser in pain relief, we irradiated 36 outpatients suffering from postherpetic neuralgia. Each patient underwent 20 trials of irradiation on several points around the painful area at a frequency of 2 or 3 times a week. The efficacy of the laser at the end of 20 trials was noticed on 88.9%, and the degree of pain relief was 55.3%, which correlated with the number of trials. These results suggest that the irradiation of He-Ne laser is an effective and safe treatment for postherpetic neuralgia.

Epidural anesthesia for patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by pathologic degeneration of the lower motor neurons, motor nuclei of the caudal brainstem, and the descending pathways of the upper motor neurons. Progressive muscular atrophy and bulbar palsy with fasciculations are its clinical manifestations. Atrophy and weakness of respiratory muscles eventually lead to respiratory failure and death. The impairment of respiratory function, together with the weakened upper airway muscles, may affect anesthetic management. The response to muscle relaxants, either depolarizing or nondepolarizing, is also altered in ALS. Patients with ALS require special care throughout the perioperative period. The following case reports illustrate the safety and usefulness of epidural anesthesia in patients with ALS.

Different effects of halothane and enflurane on diaphragmatic contractility in vivo.

We examined the effects of halothane and enflurane on diaphragmatic contractility in 12 anesthetized, mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. Animals were randomly assigned to two groups, a halothane group (n = 6) and an enflurane group (n = 6). The Pdi stimulus-frequency relationship was compared at anesthetic levels of 1, 1.5, and 2 MAC (minimum alveolar concentration) in each group. The sequence of changing anesthetic concentration was randomized. In addition, the Pdi- frequency relationship was also compared between 1 MAC of halothane and enflurane in 8 of 12 dogs. In animals anesthetized with enflurane, Pdi significantly decreased with 50− and 100-Hz stimulation in the presence of increasing MAC values, whereas Pdi at10-Hz stimulation was not affected by the depth of anesthesia. Pdi with 20-Hz stimulation during 2 MAC enflurane also decreased significantly below Pdi levels seen at 1 and 1.5 MAC. By contrast, with halothane there was no difference in Pdi at any of the stimulation frequencies during any of the three levels of anesthesia. There was no statistical difference, however, between Pdi-frequency relationships during 1 MAC of halothane and enflurane in eight animals. From these results, we conclude that halothane does not impair diaphragmatic contractility any more than enflurane does, but enflurane decreases force generation of the diaphragm at high stimulation frequencies in a dose-related fashion. This depressant effect of enflurane occurs mainly through the impairment of neuromuscular transmission and/or membrane excitability. Part of its effect is probably related, however, to the impairment of excitation-contraction coupling, as suggested by the depression of Pdi at 2 MAC in response to 20-Hz stimulation.

Time-dependent Effect of Morphine and Time-independent Effect of Mk-801, an Nmda Antagonist, on the Thermal Hyperesthesia Induced by Unilateral Constriction Injury to the Sciatic Nerve in the Rat

BackgroundIt is known that peripheral nerve injury induces time-dependent changes in dorsal horn function. The current study investigated the time dependency of the effects of intrathecal morphine and MK-801, an N-methyl-D-aspartate antagonist, on the thermal hyperesthesia evoked by unilateral constriction injury to the sciatic nerve in the rat. MethodsIn rats with a unilateral constriction injury to the sciatic nerve, paw withdrawal latency against thermal stimulation for the injured paw was typically 3 s less than that for the uninjured paw during the first 5 weeks after the injury. Drugs were administered intrathecally 1 or 5 weeks after the nerve injury. ResultsIntrathecal morphine increased the paw withdrawal latencies of both the injured paw and the uninjured paw in an equally dose dependent manner in the 1-week study. In the 5-week study, morphine increased the paw withdrawal latency of the uninjured paw in a dose-dependent manner, but not that of the injured paw. Intrathecal MK-801 increased the paw withdrawal latency of the injured paw to the level of the uninjured paw in a dose-dependent manner in both the 1− and 5-week studies. ConclusionsThese data indicate that (1) an N-methyl-D-aspartate receptor-mediated spinal facilitation may be the common mechanism maintaining the thermal hyperesthesia evoked by the constriction injury, and (2) the effects of intrathecal morphine on this thermal hyperesthesia are time-dependent.

Diaphragmatic function during sevoflurane anaesthesia in dogs

The effect of increasing the concentration of sevoflurane anaesthesia on diaphragmatic function was investigated in six mechanically ventilated dogs. Diaphragmatic function was assessed by measuring the transdiaphragmatic pressure (Pdi) generated during bilateral supramaximal stimulation of the cervical phrenic nerves at frequencies of 0.5, 10, 20, 50, and 100 Hz under quasi-isometric conditions. Measurements were performed at 1, 1.5 and 2 MAC concentrations after maintaining stable conditions for one hour. The Pdi-stimulus frequency relationship was compared at each anaesthetic concentration. The sequence of changing anaesthetic depth was altered in random fashion among animals. The Pdi amplitude generated by single twitch (0.5 Hz) was unchanged at the three concentrations. In addition, no change in Pdi during 10, 20, 50 Hz stimulation was noted at any of the three levels of anaesthesia. By contrast, Pdi with 100 Hz stimulation during 2 MAC sevoflurane exposure (28.1 ±5.0 cmH2O) decreased below Pdi levels seen at 1 and 1.5 MAC (35.3 ±4.3 cmH2O and 31.5 ±4.3 cmH2O, respectively) (P < 0.05). From these results, we conclude that sevoflurane impairs diaphragmatic function in deep anaesthesia.RésuméL’effect d’une augmentation de la concentration de sevoflurane sur la fonction diaphragmatique a été investigué chez six chiens ventillés mécaniquement. La fonction diaphragmatique a été évaluée en mesurant la pression trans-diaphragmatique (Pdi) développée durant la stimulation supramaximale bilatérale des nerfs phréniques cervicaux à des fréquences de 0,5, 10, 20, 50, et 100 Hz durant les conditions quasi-isométriques. Les mesures ont été faites à 1, 1,5 et 2 MAC après le maintien d’une condition stable pour une heure. La relation entre la Pdi et la fréquence de la stimulation a été comparée avec chaque concentration de l’anesthésique. La fréquence du changement de la profondeur de l’anesthésie a été altérée d’une façon randomisée parmi les animaux. L’amplitude de la Pdi générée par une stimulation de 0,5 Hz a été inchangée aux trois différentes concentrations. En plus, aucun changement dans la Pdi durant la stimulation à 10, 20 et 50 Hz n’a été noté avec les trois niveaux de l’anesthésie. Par contre, la Pdi avec une stimulation de 100 Hz durant l’exposition à 2 MAC de sevoflurane (28,1 ±5,0 cm H2O) a diminué en bas des niveaux de Pdi observés à 1 et 1,5 MAC(35,3 ±4,3 cm H2O et 31,5 ±4,3 cm H2O, respectivement) (P < 0,05). A partir de ces résultats, on conclut que le sevoflurane altère la fonction diaphragmatique lors d’une anesthésie profonde.

Heat shock protein 70 messenger Rna reflects the severity of ischemia/hypoxia-reperfusion injury in the perfused rat liver

OBJECTIVES To determine whether ischemia-reperfusion and hypoxia-reoxygenation cause cellular damages and stress responses in an isolated perfused rat liver model. To determine whether the increased synthesis of stress protein messenger RNA reflects cellular injury. DESIGN Prospective, controlled study. SETTING Institutional laboratories. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Isolated rat livers with cell free perfusion were exposed to various periods of ischemia-reperfusion or hypoxia-reoxygenation. MEASUREMENTS AND MAIN RESULTS We measured hepatic oxygen consumption and alanine aminotransferase leakage from liver during perfusion. We analyzed the gene expression of heat shock protein 70, a major stress protein, of the liver by Northern blotting after perfusion. The expression of heat shock protein 70 messenger RNA augmented as the reperfusion period increased. The expression level after graded ischemia or hypoxia significantly correlated with the calculated hepatic oxygen debt (r2 = .737; p < .001; n = 21), or with the accumulated alanine aminotransferase leakage from the liver (r2 = .509; p < .001; n = 21). CONCLUSIONS These results suggest that the accumulation of heat shock protein 70 messenger RNA reflects the severity of ischemia-reperfusion and hypoxia-reoxygenation injuries, and that a stress response in reperfusion can be triggered without formed elements of blood.