GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents.

PURPOSE: The purpose of this study was to investigate the role of the group III/IV muscle afferents in the bioenergetics of exercising skeletal muscle beyond constraining the magnitude of metabolic perturbation. METHODS: Eight healthy men performed intermittent isometric knee-extensor exercise to task failure at ~58% maximal voluntary contraction under control conditions (CTRL) and with lumbar intrathecal fentanyl to attenuate group III/IV leg muscle afferents (FENT). Intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate (H2PO4), adenosine triphosphate (ATP), and pH were determined using phosphorous magnetic resonance spectroscopy (P-MRS). RESULTS: The magnitude of metabolic perturbation was significantly greater in FENT compared with CTRL for [Pi] (37.8 ± 16.8 vs 28.6 ± 8.6 mM), [H2PO4] (24.3 ± 12.2 vs 17.9 ± 7.1 mM), and [ATP] (75.8% ± 17.5% vs 81.9% ± 15.8% of baseline), whereas there was no significant difference in [PCr] (4.5 ± 2.4 vs 4.4 ± 2.3 mM) or pH (6.51 ± 0.10 vs 6.54 ± 0.14). The rate of perturbation in [PCr], [Pi], [H2PO4], and pH was significantly faster in FENT compared with CTRL. Oxidative ATP synthesis was not significantly different between conditions. However, anaerobic ATP synthesis, through augmented creatine kinase and glycolysis reactions, was significantly greater in FENT than in CTRL, resulting in a significantly greater ATP cost of contraction (0.049 ± 0.016 vs 0.038 ± 0.010 mM·min·N). CONCLUSION: Group III/IV muscle afferents not only constrain the magnitude of perturbation in intramuscular Pi, H2PO4, and ATP during small muscle mass exercise but also seem to play a role in maintaining efficient skeletal muscle contractile function in men.

Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats.

RATIONALE: By acting on peripheral opioid receptors, opioid agonists can attenuate nociceptive responses induced by a variety of agents. OBJECTIVES: This study was conducted to characterize capsaicin-induced thermal hyperalgesia in rats and to evaluate the hypothesis that local administration of either mu or kappa opioid agonists (fentanyl and U50,488, respectively) can attenuate capsaicin-induced nociception. METHODS: Capsaicin was administered s. c. in the tail of rats to evoke a nociceptive response, which was measured by the warm-water tail-withdrawal procedure. Either fentanyl or U50,488 was co-administered with capsaicin in the tail to evaluate local antinociceptive effects. In addition, the local antagonism study was performed to confirm the site of action of both opioid agonists. RESULTS: Capsaicin (0.3-10 microg) dose dependently produced thermal hyperalgesia manifested as reduced tail-withdrawal latencies in 45 degrees C water. Co-administration of either fentanyl (0.32-3.2 microg) or U50,488 (10-100 microg) with capsaicin (3 microg) attenuated capsaicin-induced hyperalgesia in a dose-dependent manner. Furthermore, this local antinociception was antagonized by small doses (10-100 microg) of an opioid antagonist, quadazocine, applied s.c. in the tail. However, the locally effective doses of quadazocine, when applied s.c. in the back (i.e., around the scapular region), did not antagonize either fentanyl or U50,488. CONCLUSIONS: In this experimental pain model, activation of peripheral mu or kappa opioid receptors can attenuate capsaicin-induced thermal hyperalgesia in rats. It supports the notion that peripheral antinociception can be achieved by local administration of analgesics into the injured tissue without producing central side effects.

The effects of thiopental sodium on fentanyl-induced muscle rigidity in a human model.

STUDY OBJECTIVE: To describe a safe human model in which to study the treatment of fentanyl-induced muscle rigidity and report on the efficacy of thiopental sodium for this purpose. DESIGN: Randomized, observer-blinded comparison of regimens. SETTING: Inpatient surgery at a university-affiliated teaching hospital. PATIENTS: Thirty patients scheduled for elective surgery in whom the administration of high-dose fentanyl was felt to be appropriate and who experienced severe muscle rigidity in the chest, abdomen, and upper extremities after the fentanyl was administered. INTERVENTIONS: One arm was isolated from circulation with a blood pressure (BP) cuff inflated to 100 mmHg above systolic blood pressure (SBP), after which fentanyl 25 to 50 micrograms/kg was administered intravenously (IV) at a rate of 1 mg/min in the contralateral arm. If severe muscle rigidity became apparent in three muscle groups (the chest, abdomen, and arms), patients were either (1) observed for 3.5 minutes without further intervention, (2) given thiopental sodium 1.5 mg/kg IV, followed 120 seconds later by succinylcholine 1 mg/kg IV, or (3) given succinylcholine 1 mg/kg IV, followed 120 seconds later by thiopental sodium 1.5 mg/kg IV. MEASUREMENTS AND MAIN RESULTS: A single observer, blinded to the technique, evaluated and recorded the degree of muscle rigidity present in the chest wall, abdomen, and upper extremities (one isolated from the circulation by a tourniquet) 90 seconds and 3.5 minutes after the onset of muscle rigidity in the control group and 90 seconds after the administration of either thiopental sodium or succinylcholine in the two experimental groups. The observer was the same individual in all instances. The muscle rigidity associated with the administration of high-dose fentanyl was clinically attenuated by the administration of thiopental sodium, especially in the extremities. Succinylcholine was more effective than thiopental sodium in producing muscle flaccidity in all muscle groups not isolated by a tourniquet. In no case did the muscle rigidity compromise our ability to oxygenate the patient adequately. CONCLUSIONS: Thiopental sodium does blunt the degree of muscle rigidity induced by high-dose fentanyl, though not as effectively as does succinylcholine. One can safely isolate an extremity prior to the administration of high-dose fentanyl and a muscle relaxant, intubate the trachea, and ventilate a patient, while retaining the ability to study the effect of centrally acting drugs on fentanyl-induced rigidity in the isolated extremity.

[Naloxone--a clinical study on dosage (author's transl)]. / Naloxon. (Eine klinische Untersuchung zur Frage der Dosierung).

In 50 Patients (group I) anaesthetized with neuroleptanalgesia and in 20 patients (group II) anaesthetized with moderate doses of fentanyl given to supplement nitrous oxide - halothane anaesthesia the postoperative respiratory depression was antagonized with naloxone. Each patient was carefully titrated with small increments of naloxone (40 microgram) given in 1-2 minute intervals. A reversal of the narcotic induced respiratory depression was taken for granted, when respiratory rate exceeded 12/min, tidal volume and blood gas analysis showed normal values. The results demonstrated a correlation between the need for naloxone and the time interval from the last administration of fentanyl to the completion of the operation and the fentanyl consumption per hour. When the interval was less than 1 hour more than 90% of the patients required postsurgical naloxone for respiratory inadequacy. The mean naloxone dose was 20 to 30% of the fentanyl dose given per hour: 1,2 microgram/kg naloxone reversed 4,9 microgram/kg.h fentanyl (group I) and 0,6 microgram/kg naloxone reversed 2,9 microgram/kg.h fentanyl (group II) respectively. To prevent renarcotization it is recommended to administer naloxone i.m. 30 to 45 min after the last naloxone-injection using the total i.v. dose.