NMDA antagonist modulation of morphine antinociception in female vs. male rats

NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague–Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 °C hotplate and tail withdrawal assays 15–120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.     

Extreme hyperthermia induced in cats by the enkephalin analog FK 33-824

FK 33-824 [H₂N-Tyr-D-Ala-Gly-MePhe-Met(O)-OH] was injected into the third cerebral ventricle of unrestrained cats. Doses of 0.25–4 μg induced dose-related increases in body temperature. Hyperthermic responses to 1 μg of the peptide were greater the warmer the environment. Naloxone given intraventricularly 1 hr after FK 33-824 (1 μg) reduced the hyperthermia. In 12 tests with six cats FK 33-824 (1–25 μg) increased temperature 4.2–4.7°C. These marked responses were also inhibited by naloxone, but two cats died when administration of antagonist was delayed for 80 min to 3 hr after attainment of maximal body temperature. Larger doses of FK 33-824 (50–250 μg) evoked little increase in temperature, indicative of a separate action to depress thermoregulation. Although responses to FK 33-824 were antagonized by naloxone, this peptide, like another enkephalin analog D-Ala²-Met-enkephalinamide, must act on receptors which are not affected by morphine since (1) the hyperthermic response to FK 33-824 varied with environmental temperature, whereas the response to morphine does not, and (2) high doses of FK 33-824 depressed thermoregulation, an activity not shared by morphine in the cat. Furthermore, the maximal increases in temperature after FK 33-824 injection were greater than those evoked by either morphine or D-Ala²-Met-enkephalinamide. This observation provides evidence for an additional subset of naloxone-sensitive, ν, receptors, stimulation of which can influence thermoregulation in the cat.     

Opioid activities of human β-casomorphins

Summary Opioid activities of human -casomorphin-4,-5,-7 and -8 and, for comparison, of the corresponding bovine -casomorphins were studied in the guinea-pig ileum preparation. Binding parameters, i.e. K _d -values and binding site concentrations, for the interaction of human and bovine -casomorphins with opioid receptors in rat brain homogenates were determined in inhibition experiments, using [³H]-(d-Ala², MePhe⁴, Gly-ol⁵)enkephalin, [³H]-(d-Ala², d-Leu⁵)enkephalin and [³H]ethylketazocin as -, - and -opioid receptor ligands. Analysis of binding data was performed using a non-linear curve fitting program. All -casomorphins examined displayed opioid activity. The affinity was highest for -receptors, less so for -receptors and lowest for -receptors. It is suggested that human -casomorphins might play a role as food hormones.     

Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal

Previously, we demonstrated that two nonselective inhibitors of nitric oxide synthase (NOS),l-N ^G-nitroarginine (l-NNA) andl-N ^G-nitroarginine methyl ester (l-NAME), reduced some signs of morphine withdrawal in rats. The present work extended these studies to include 7-nitroindazole (7-NI), an inhibitor specific for cerebral NOS, andN(5)-(1-iminoethyl)-l-ornithine (l-NIO), a potent inhibitor of endothelial NOS. Behavioral effects of these four NOS inhibitors and clonidine, an ₂-adrenoceptor, agonist, on morphine withdrawal in rats were assessed. Rats received one 75-mg morphine pellet subcutaneously (SC). Three days later, NOS inhibitors were administered IP 1 h before withdrawal was precipitated with naloxone (0.5 mg/kg, SC) and scored. 7-NI,l-NIO,l-NAME andl-NNA produced dose-related decreases in weight loss, diarrhea, wet dog shakes and grooming. 7-NI also reduced mastication, salivation and genital effects. Clonidine produced effects similar to 7-NI. In awake, morphine-naive and morphine-dependent rats not subjected to withdrawal, 7-NI was the only NOS inhibitor that did not increase blood pressure. Because 7-NI attenuated more signs of opioid withdrawal thanl-NNA,l-NAME orl-NIO without causing hypertension, 7-NI appears to warrant further testing as a potential candidate for human use.Abstracts were presented at the annual meetings of the College on Problems of Drug Dependence, West Palm Beach, Fla., 18–23, June 1994; International Narcotics Research Conference, North Falmouth, Cape Cod, Mass., 16–21, July 1994; and a Satellite Symposium to IUPHAR, Montreal, Canada, 22–24, July 1994.     

Reflex peristalsis in the guinea pig isolated ileum is endogenously controlled by kappa opioid receptors

Summary (1) Reflex peristalsis in the circular muscle of the guinea pig ileum was elicited in vitro by sustained luminal distension of the intestinal wall according to 2 cm H₂O and evaluated in terms of the number of peristaltic waves within 15 min intervals. (2) The poorly -selective opioid antagonist naloxone at concentrations of 10^–7 and 10^–6 mol/l increased the frequency of peristaltic contractions within the first 15 min interval, and thereafter in a declining fashion, by 68 and 88%, respectively. The highly -selective opioid antagonist nor-binaltorphimine behaved similarly. It was, by one order of magnitude, more potent but a little less effective than naloxone, i.e., the maximum effect was 57% increase in peristaltic frequency at 10^–8 mol/l. Concentrations of 10^–7 and 10^–6 mol/l had the same effect as 10^–8 mol/l, and 10^–9 mol/l were ineffective. The highly -selective antagonist CTOP-NH₂ and the highly -selective antagonist ICI 174,864 were ineffective up to 10^–6 mol/l. (3) It is concluded that predominantly opioid receptors are used by endogenous opioids under the present conditions to inhibit reflex peristalsis.     

我国门诊癌症患者阿片类镇痛药使用的现状研究

摘 要 目的：分析我国门诊癌症患者阿片类镇痛药的使用情况。方法：从医院处方分析合作项目数据库中随机提取我国5个城市89家医院门诊癌痛患者2016年中40 d的使用阿片类镇痛药处方数据,对其用药频度（DDDs）及限定日费用（DDC）、总费用等指标进行分析。 结果：共纳入13 803例患者的阿片类镇痛药处方,其中男8 522例,患者年龄分布在3~96岁。按照阿片类镇痛药使用人次由多到少的顺序排列依次为羟考酮及其复方制剂、曲马多及其复方制剂、可待因及其复方制剂、吗啡和芬太尼。羟考酮及其复方制剂的处方总金额和DDDs均最高。口服是最主要的给药途径,人次占比和金额占比分别为86.6%和83.3%。结论：阿片类镇痛药使用的基本面比较合理,但是在部分药品使用方面与国外情况有所区别,其合理性需要通过处方点评等方法进行进一步研究。     

A Stage I pilot study of acceptance and commitment therapy for methadone detoxification

Background

While agonist replacement therapies are effective for managing opioid dependence, community treatment programs are increasingly choosing detoxification. Unfortunately, success rates for opioid detoxification are very low, in part, due to physical and psychological symptoms associated with opioid withdrawal. Few behavior therapies specifically address the distressing experiences specific to opioid withdrawal. A novel behavioral treatment, acceptance and commitment therapy (ACT), works from the premise that the avoidance of unpleasant private experiences (thoughts, feelings, bodily sensations) is ubiquitous yet may be pathogenic, resulting in treatment drop-out and further drug use.

Methods

This Stage I pilot study developed and tested an ACT-based opioid detoxification behavioral therapy. Opioid dependent patients (N = 56) who were attending a licensed methadone clinic were randomized to receive either 24 individual therapy sessions of ACT or drug counseling (DC) in the context of a 6-month methadone dose reduction program.

Results

While no difference was found on opioid use during treatment, 37% of participants in the ACT condition were successfully detoxified at the end of treatment compared to 19% of those who received DC. Fear of detoxification was also reduced across time in the ACT condition relative to DC.

Conclusion

This first study of ACT to assist opioid detoxification indicates promise. Research is needed to refine specific treatment strategies for this population to further strengthen effects.     

The toxic effect of opioid analgesics on human sperm motility in vitro

Opioid analgesics are the most common therapeutic analgesic for acute pain. In this study, the toxicological and pharmacological features of a group of opioid analgesics were characterized by the motility of human sperm. Aliquots of sperm were incubated with various concentrations of opioid analgesics in vitro. Computer-assisted sperm analysis was used to assess sperm motility at 15 minutes, 2 hours, and 4 hours after drug addition to the medium. Butorphanol and dezocine showed marked reduction of motility after incubation with sperm for 15 minutes. Butorphanol was more effective than dezocine in immobilizing sperm. Other opioids studied, such as fentanyl, alfentanil, and sufentanil, showed only partial inhibitory activity. Based on the data reported herein, we have found that butorphanol and dezocine exert a sperm-immobilizing effect. However, fentanyl, alfentanil, and sufentanil exhibit only partial inhibition of sperm motility. Given the increasing use of opioids and their potential effect on sperm motility, these findings are greatly relevant to male reproductive health.