Supraspinal neurotensin-induced antianalgesia in mice is mediated by spinal cholecystokinin.
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Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCK(A)-receptor antagonist (10-1000 ng), and PD135,158, a CCK(B)-receptor antagonist (250-500 ng), also eliminated the antianalgesic action of neurotensin. Thus, the mechanism of the antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the antianalgesic action of supraspinal pentobarbital which also involves spinal CCK. (+info)
Effects of Tyr-MIF-1 on stress-induced analgesia and the blockade of development of morphine tolerance by stress in mice.
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The role of Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) in biological responses to stress exposure was examined in mice. Intraperitoneal or intracerebroventricular administration of Tyr-MIF-1 attenuated not only footshock (FS)- and forced swimming (SW)-stress-induced analgesia (SIA) but also socio-psychological (PSY)-SIA that, when using the communication box, is produced without any direct physical nociceptions. Tyr-MIF-1 also disrupted the suppressive effect of concurrent exposure to FS- and PSY-stress on the development of morphine antinociceptive tolerance. In elevated-plus-maze tests, mice treated with Tyr-MIF-1 tended to spend more time in the open arms compared with the control group, suggesting the anxiolytic properties of the peptide. Thus, the finding that Tyr-MIF-1 modulates these stress responses suggests that the peptide regulates an endogenous biological alert system responding to stress exposure, perhaps, counteracting the excessive response of the system. Furthermore, Tyr-MIF-1, in the case of PSY-stress, through the attenuation of emotional factors such as fear and anxiety, may suppress PSY-SIA and inhibition by PSY-stress of the development of morphine tolerance. (+info)
Intra-articular morphine and/or bupivacaine after total knee replacement.
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The postoperative analgesic effects of intra-articular injections of bupivacaine and/or morphine were examined prospectively in 437 patients who had total knee replacement for osteoarthritis. They were divided randomly into four groups. Group I received 10 mg of morphine (1 ml) and 9 ml of saline, group II received 10 ml of bupivacaine (2.5 mg/ml), group III received 10 ml of saline, and group IV received 10 mg of morphine (1 ml) and 9 ml of bupivacaine (2.5 mg/ml). All analgesics administered in the first 24 hours after operation were recorded. The patients rated their pain on the McGill-Melzack scale at 1, 6, 12 and 24 hours. No significant differences were found between any of the groups in the use of Demoral and/or Toradol in 24 hours, the length of stay in hospital or the pain rating at 1, 6, 12 or 24 hours. Patients in groups I and IV, whose injections included morphine, used significantly more morphine in the first 24 postoperative hours than did groups II or III. (+info)
Metabolism of remifentanil during liver transplantation.
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We have investigated the pharmacokinetics of remifentanil and its less potent metabolite, GR90291, in six adult patients undergoing orthotopic liver transplantation (OLT). A single bolus infusion of remifentanil 10 micrograms kg-1 min-1 was given at the beginning of the dissection and anhepatic phases of OLT. Remifentanil and GR90291 concentrations were measured in subsequent serial arterial and mixed venous blood samples. Mean arterial clearance of remifentanil was significantly greater (P = 0.02) in the dissection phase (79.54 ml min-1 kg-1) than in the anhepatic phase (39.57 ml min-1 kg-1). Steady state volumes of distribution were not significantly different. Clearance of remifentanil during the anhepatic phase was similar to that of healthy adult patients. Mean maximum concentration (Cpmax) of GR90291 was lower in the dissection phase than in the anhepatic phase (P = 0.026). There was no significant pulmonary metabolism of remifentanil. (+info)
Continuous epidural infusion of ropivacaine for postoperative analgesia after major abdominal surgery: comparative study with i.v. PCA morphine.
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We have compared the quality of three regimens of postoperative analgesia (continuous epidural administration of ropivacaine (Ropi. group), epidural ropivacaine and patient-controlled analgesia (PCA) with i.v. morphine (Ropi. + PCA group) and PCA morphine alone (PCA group)) during the first postoperative 24 h in a multicentre, randomized, prospective study. Postoperative analgesia was studied in 130 patients after major abdominal surgery performed under general anaesthesia. The ropivacaine groups received 20 ml of epidural bolus ropivacaine 2 mg ml-1 via the epidural route at the end of surgery, followed by continuous infusion of 10 ml h-1 for 24 h. The Ropi. + PCA group also had access to i.v. PCA morphine 1 mg, with a 5-min lockout. The PCA group received morphine as the sole postoperative pain treatment. The two ropivacaine groups had lower pain scores (P < 0.01) than the PCA group. Morphine consumption was higher in the PCA group (P < 0.05) than in the two ropivacaine groups. The quality of pain relief was rated as good or excellent in 79-85% of patients in the three groups. The percentage of patients without motor block increased between 4 and 24 h from 61% to 89% in the Ropi. group, and from 51% to 71% in the Ropi. + PCA group. (+info)
Opioid receptor independent effects of morphine on membrane currents in single cardiac myocytes.
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We have examined the effects of morphine, a mu-opioid receptor agonist, on various membrane ionic currents in rat ventricular and human atrial myocytes, using patch-clamp techniques in the whole-cell configuration. Morphine produced a concentration-dependent reduction in peak transient sodium current. When the sodium current (INa) was evoked at 5-s intervals the estimated IC50 for morphine was approximately 30 mumol litre-1. Morphine 10 mumol litre-1 inhibited INa with a 5-mV shift in the potential-dependent inactivation curve to negative potentials and retarded the INa recovery rate from the inactivated state. Use-dependent INa block was not observed when INa was elicited at frequencies varying from 0.2 to 20 Hz. Morphine did not significantly affect the inward calcium current (ICa), transient outward current (Ito) or the inwardly rectifying potassium current (IK1) at a concentration of 30 mumol litre-1. The inhibitory effect of morphine on INa could not be prevented or reversed by treatment with the opioid antagonist naloxone. Therefore, we suggest that morphine can directly inhibit the Na+ inward current and bind to inactivated Na+ channels. (+info)
Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification.
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The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta9-THC) were evaluated using the tail-flick test. Morphine preceded by Delta9-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED50 value when administered after Delta9-THC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone and hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, l-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta9-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta9-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta9-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta9-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta9-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception. (+info)
Relative potency of levo-alpha-acetylmethadol and methadone in humans under acute dosing conditions.
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levo-alpha-Acetylmethadol (LAAM) and methadone are full mu-opioid agonists used to treat opioid dependence. Current labeling indicates that LAAM is less potent than methadone. Clinical studies have not determined the relative potency of these drugs. This study compared the effects of acute doses of LAAM and methadone and also examined the ability of naloxone to reverse their effects. Five occasional opioid users received once weekly doses of either placebo, LAAM, or methadone (15, 30, or 60 mg/70 kg p.o.) in agonist exposure sessions and then received naloxone (1.0 mg/70 kg i.m.) 24, 72, and 144 h after agonist exposure. Subject-rated, observer-rated, and physiological measures were assessed regularly. Comparisons of physiological and subjective measures collected in agonist exposure sessions indicate that LAAM is not less potent than methadone under acute dosing conditions. For some measures, LAAM was significantly more potent. Three subjects who entered the study were withdrawn for safety reasons due to greater than anticipated and clinically relevant respiratory depression after receiving 60 mg of LAAM. Naloxone did not fully reverse the pupil constriction produced by 60 mg of LAAM. Acute agonist effects suggest that LAAM may be more potent than methadone and more potent than current labeling indicates. An accurate LAAM:methadone relative potency estimate will aid determination of adequate doses for opioid-dependent patients inducted onto LAAM and for methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM. (+info)