Nagasaka H

Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint

Background Three types of opioid receptors, micro, delta, and kappa, are present in the periphery and in the central nervous system. In contrast to the effects in the central nervous system, the antinociceptive action of opioids in the periphery is not as well characterized. The effects of intraarticular, spinal, and intramuscular injections of micro, delta, and kappa opioid agonists on the autonomic response evoked by compression of an inflamed knee joint were evaluated. Methods In halothane‐anesthetized rats, arthritis was induced by injecting kaolin and carrageenan into the right knee joint. Standardized compression of the knee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus‐dependent hypertension (Delta = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. The drug injection was performed 4 hr after induction of the inflammation. Results The intrathecal administration of micro, delta, and kappa agonists resulted in a dose‐dependent blockade of the cuff‐evoked increase in blood pressure. The order of intrathecal drug activity on the compression‐evoked blood pressure responses with median effective dose (ED50) was sufentanil (0.02 nmol; micro) > PD117302 (0.5 nmol; kappa); spiradoline (1.5 nmol; kappa) morphine (2.4 nmol; micro) > DADL (15 nmol; delta); DPDPE (18 nmol; delta) > U‐50,488H (620 nmol; kappa) > naloxone = 0. The intraarticular administration of micro and kappa, but not delta agonists, produced a dose‐dependent blockade of a compression‐evoked increase in blood pressure, with the order of drug activity (ED50) as follows: sufentanil (0.04 micro mol) > PD117302 (0.3 micro mol); spiradoline (0.8 micro mol), morphine (0.9 micro mol) > U‐50,488H (0.9 micro mol) > DPDPE (> 5 micro mol); DADL (> 18 micro mol) > naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 micro mol) > PD117302 (2 micro mol); spiradoline (11 micro mol) morphine (9 micro mol) > DPDPE (> 5 micro mol); DADL (18 micro mol) > U‐50,488H (22 micro mol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with the ordering of naloxone potency against equiactive doses of morphine > U50,488H. Conclusions The activity of the respective agonists and the intraarticular > intramuscular ordering of systemic potency in this model indicate that opioids, by an action at micro and kappa, can exert a direct antihyperalgesic action at the terminals of primary afferents projecting to a region of inflammation. These observations offer strong support for a peripheral action of opioids in certain states in inflammation‐induced hyperalgesia.

PHARMACOLOGY OF INTRATHECAL ADRENERGIC AGONISTS : CARDIOVASCULAR AND NOCICEPTIVE REFLEXES IN HALOTHANE-ANESTHETIZED RATS

The effects of intrathecally administered adrenergic agonists (alpha-1-methoxamine, alpha-2-dexmedetomidine, clonidine, and ST-91, beta-isoproterenol) on nociceptive (tail-flick reflex) and cardiovascular changes (blood pressure and heart rate) evoked by immersing the tail in 53 degrees C water were examined in rats anesthetized with halothane (0.75%) and in which intrathecal catheters had been chronically implanted. Administration of intrathecal alpha-2, but not alpha-1 or beta agonists, produced a dose-dependent block of the tail-flick and evoked cardiovascular responses with the order of activity being as follows: dexmedetomidine greater than clonidine greater than ST-91 much greater than methoxamine greater than or equal to isoproterenol. These effects were readily reversed by the alpha-2 antagonist idazoxan. Intravenously administered dexmedetomidine at a dose that is active when given intrathecally (0.33 micrograms) was without effect on either the tail-flick or the evoked cardiovascular responses. Without drugs, the halothane MAC was 1.23 +/- 0.07%. In the presence of intrathecally administered dexmedetomidine (0.33 micrograms), the MAC was significantly reduced to 0.9 +/- 0.09%. The intrathecal administration of alpha-2 agonists resulted in a rapid decrease in resting blood pressure and heart rate with the magnitude of hypotension being as follows: dexmedetomidine greater than clonidine greater than ST-91. These data suggest a potent spinal alpha-2-receptor-mediated modulation of somatomotor and autonomic responses to pain.

Comparative Analysis of Apoptosis-inducing Activity of Codeine and Codeinone

Background There are relatively few studies about the antiproliferative effects of codeine-related compounds on human cancer cell lines, compared with those of morphine-related compounds. The authors previously found that codeinone, an oxidation metabolite of codeine, among 10 opioids, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) against human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-l-cysteine (NAC). These findings prompted us to perform a more detailed study of apoptosis induction after codeinone treatment. Methods Apoptosis was induced by treating HL-60 cells for 1–6 h with codeine or codeinone. DNA fragmentation was assessed by both agarose gel electrophoresis and fluorometric determination of the fragmented DNA after staining with diamidinophenylindole (DAPI). The appearance of apoptotic cells was monitored by microscopic observation after staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS) after staining with Annexin. The release of cytochrome c and cytochrome oxidase from mitochondria and activation of caspase 3 were monitored by Western blot analysis. Intracellular caspase 3–like activity was confirmed by FACS, using cell permeable substrate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNA expression were assayed by activity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Results Codeinone induced internucleosomal DNA fragmentation and production of Annexin-positive apoptotic cells more potently than codeine in HL-60 cells. Codeinone stimulated the release of both cytochrome c and cytochrome oxidase, and cleavage of procaspase 3 without significant changes in both the activity and expression of MnSOD. Conclusions Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiating its antitumor potential.

Effects of intrathecal mu, delta, and kappa agonists on thermally evoked cardiovascular and nociceptive reflexes in halothane-anesthetized rats.

Despite significant opioid binding in the intermediolateral cell column, the effects of intrathecal injections of mu, delta, and kappa opioid agonists on the cardiovascular response to noxious stimulation have not been examined systematically. The pharmacology of intrathecally administered opioid agonists (mu, morphine, [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAGO); delta, metkephamid, [D-Ala2-D-Leu5]enkephalin (DADL), [D-Pen2,D-Pen5]enkephalin (DPDPE); kappa, U50488H and PD117,302) or agonist-antagonist (nalbuphine) on somatomotor (tail-flick) and cardiovascular changes (blood pressure and heart rate) evoked by immersing the tail in 53 degrees C water were examined in rats anesthetized with halothane (0.75%) and in which intrathecal catheters had been chronically implanted. Intrathecal administration of mu and delta, but not kappa agonists or agonist-antagonist produced a dose-dependent block of tail-flick and evoked cardiovascular responses with the order of activity being as follows: DAGO > metkephamid DADL > morphine > DPDPE >> nalbuphine = PD117,302 = U50488H = 0. These effects were reversed readily by the opioid antagonist naloxone. In addition, intrathecal administration of mu and delta but not kappa or agonist-antagonist had little effect on resting heart rate and blood pressure. These data indicate that the agonist occupancy of spinal mu and delta, but not kappa agonists can profoundly modulate the autonomic and somatomotor response evoked by high threshold thermal stimuli.

The effects of ketamine on the excitation and inhibition of dorsal horn WDR neuronal activity induced by bradykinin injection into the femoral artery in cats after spinal cord transection

BackgroundIt is now well established that wide dynamic range neurons (WDR) can possess widespread cutaneous inhibitory receptive fields, as well as excitatory receptive fields, in specific regions of the body. The ability of ketamine to depress the excitatory responses of spinal WDR neurons indicates that the analgesia produced by this agent may be a result, in part, of this spinal action. The primary purpose of this study was to investigate the effects of ketamine on the WDR pro-priospinal inhibitory mechanism that is induced by a bradykinin (BK) injection as a noxious test stimuli. MethodsIn decerebrate, spinal cord-transected cats (L1-L2), the effects of a low (0.5 mg·kg-1, intravenous) and a high (10 mg·kg-1, intravenous) dose of ketamine on the neuronal activity of spinal dorsal horn WDR neurons evoked by femoral artery injection of BK (10 μg) was examined. Extracellular activity was recorded from single WDR neurons that responded to noxious and innocuous stimuli applied to the cutaneous receptive fields on the foot pads of the left hind paw. ResultsAfter ipsilateral BK administration, the activity of the WDR neurons was found to be increased (excited) in all ten neurons that were examined. In contrast, the activity of these neurons was found to be decreased (inhibited) in five of these ten neurons after BK administration into the contra-lateral femoral artery. The 10 mg·kg-1 dose of ketamine significantly suppressed the excitatory activity observed in all 15 of the WDR neurons examined. A comparison of the effects produced by the 0.5-mg·kg-1 and the 10-mg·kg-1 Intravenous doses reveals that the amount of suppression was dose-related. In addition, the inhibitory WDR neuronal activity induced by contralateral BK injection was also significantly reduced by both the 0.5− and the 10-mg·kg-1 doses of ketamine. ConclusionsThese results indicate that this reduction of excitatory and inhibitory responses of WDR neurons after noxious stimulation is likely to be the fundamental basis for the spinal cord component of ketamine-induced analgesia.

Effects of fentanyl on cardiovascular and plasma catecholamine responses in surgical patients

AbstractPurpose. Whether opioids administered before skin incision, under inhalational anesthesia, improve cardiovascular and plasma catecholamine responses to surgical stimulation compared with those administered after skin incision remains unclear. We compared the effects of fentanyl injected before and after skin incision on these responses. Methods. We studied 50 healthy female patients [American Society of Anesthesiologist (ASA) physical status 1] who underwent elective total abdominal hysterectomy through an infraumbilical incision (midline incision) under nitrous oxide (60%)–oxygen–isoflurane (1.2%) anesthesia. Fentanyl (2.0 or 4.0 μg·kg−1) was administered IV 5 min before (pretreatment group) or 5 min after (posttreatment group) skin incision. Control patients received a saline injection. Heart rate (HR) and mean arterial blood pressure (MAP) were recorded 1 min before incicsion and serially for 30 min afterward. Plasma levels of norepinephrine (Nor) and epinephrine (Epi) were determined 1 min before incision and serially up to 20 min after skin incision. Results. The MAP response to incision had decreased after 10 min in posttreatment fentanyl (2 μg·kg−1) (P < 0.05) and after 8, 10, 15, and 20 min in posttreatment fentanyl (4 μg·kg−1) (P < 0.05). At the same doses, fentanyl administered before skin incision attenuated MAP response to incision after 1 min with the smaller dose (P < 0.05) and after 1, 3, 5, 6, 8, 10, 15, and 20 min with the higher dose (P < 0.05). Fentanyl suppressed Epi response to surgery 8 and 20 min after skin incision (P < 0.05) at both doses, except for 8 min after incision in pretreatment fentanyl (2 μg·kg−1). Overall, the hemodynamic and sympathoadrenergic responses after skin incision were attenuated, with the exception of plasma Nor after fentanyl irrespective of time and dose. Conclusions. Our results indicated that fentanyl depressed cardiovascular and plasma catecholamine responses irrespective of the time of administration, and that the higher dose of fentanyl produced a greater suppression of MAP and HR responses. In addition, the depressant effects on MAP of high-dose fentanyl administered 5 min before skin incision lasted longer than when injected 5 min after incision. At both doses, the opioid attenuated the rise in plasma Epi, but not Nor.

Use of sugammadex in a patient with Charcot-Marie-Tooth disease under general anesthesia

Charcot-Marie-Tooth disease (CMT) is an inherited heterogeneous group of peripheral nerve disorders with characterized by weakness and sensory loss in the distal limbs. General anesthesia was induced with propofol, rocuronium, and remifentanil. At the end of the surgery, we administered a total of 150 mg sugammadex. The patient could lift his head and arms, open his eyes. Then we extubated tracheal tube. We successfully used sugammadex in a patient with CMT to reverse rocuronium-induced neuromuscular blockade. However, muscle relaxation might not be measured accurately in CMT patients. Thus, clinical findings should be referred to in the management of anesthesia.

F632 THE EFFECTS OF PENTAZOCINE ON THE BISPECTRAL INDEX VALUES DURING NITROUS OXIDE-SEVOFLURANE ANESTHESIA

The effect of small dose of pentazocine on the Bispectral Index(BIS)values has not been reported. In this study, we have sought to establish whether pentazocine shows a dose-dependent effect on the bispectral index values during nitrous oxide-sevoflurane anesthesia. Sixty surgical patients were enrolled in this double-blind, randomized study. Anesthesia was induced with thiopental and vecuronium and maintained with nitrous oxide-sevoflurane to target the bispectral index on approximate 40. Under stable anesthetic condition before surgery, patients were assigned to receive either a bolus of pentazocine 0.15 mg・kg, 0.3 mg・kg, or pentazocine 0.6 mg・kg at 15 min after the intubation. Fifteen minutes after the intubation, mean arterial blood pressure(MAP), heart rate 明海歯学(J Meikai Dent Med)41(1), 44−48, 2012 44

Anesthetic management of the patient with systemic lupus erythematosus and severe granulocytopenia

debrided. On the 23rd postoperative day, the wound improved. On the 30th postoperative day, the patient was discharged in good condition. Watson-Williams [2] has discussed the problems of a granulocyte count below 200 /μl before surgery. When the marrow is not hypoplastic or there is no history of unusually frequent bacterial infections, it seems reasonable to wait until evidence of infection and failure of wound recovery occurs before starting granulocyte transfusions. In our patient, the cause of granulocytopenia (150–200 /μl) was unclear and the marrow was not hypoplastic. However, we did not use granulocyte transfusions because administration of three kinds of antibiotic, sterilization with povidone iodine, and debridement were effective for peritonitis and delayed wound recovery in our patient. Although it has been reported that the administration of granulocyte colony-stimulating factor (G-CSF) increases production of granulocytes before surgery [3], in our case the administration of G-CSF was possible for only a short period before (Lenograstim; 100μg/day) and after (Filgrastim; 75μg/day) surgery because of an allergic action, i.e., fever (above 38°C). Thus, G-CSF could not be used to increase the granulocyte count in our patient. In summary, we experienced the anesthetic management of a patient with SLE and severe granulocytopenia (150–200/μl). Contrary to Watson-Williams’ discussion, we did not use granulocyte transfusions because administration of three kinds of antibiotic, sterilization with povidone iodine, and debridement were effective for peritonitis and delayed wound recovery in our patient.