小剂量MK—801加强100Hz电针抑制大鼠吗啡戒断症状的作用

目的 :观察小剂量MK 80 1(dizocilpine)是否能加强 10 0Hz电针 (electroacupuncture ,EA)抑制大鼠吗啡戒断症状的作用。方法 :大鼠皮下注射递增剂量的吗啡 5天 (每天 3次 ) ,使其对吗啡形成依赖 ,最后一次注射吗啡后 1h ,分别腹腔 (i.p .,0 .0 3mg/kg)或蛛网膜下腔 (i.t.,10 0ng/ 10 μl)注射MK 80 1,注射后 15min给予 10 0HzEA。MK 80 1注射和 10 0HzEA共进行 3次 ,两次之间相隔5h。最后一次EA结束后 30mini.p .纳洛酮 (1mg/kg)催促戒断症状 ,并观察记录 5种戒断症状的表现。结果 :(1)单纯i.p .MK 80 1仅能显著降低直立症状 ;单纯 10 0HzEA能够显著降低直立和振翼样抖动 ;i.p .MK 80 1联合 10 0HzEA能显著降低跳跃、直立、振翼样抖动和体重丢失等 4种戒断症状。 (2 )单纯i.t.MK 80 1能显著降低振翼样抖动 ;i.t .MK 80 1联合EA能显著降低上述四种戒断症状。结论 :小剂量的MK 80 1可加强 10 0HzEA抑制戒断症状的作用 ;联合使用的效果优于单纯应用EA或MK 80 1。     

多次电针刺激抑制大鼠吗啡戒断症状的累加效应及长时程后效应

目的：观察电针刺激对大鼠吗啡戒断症状的抑制作用是否有累加效应和长时程后效应。方法：用递增剂量吗啡连续皮下注射10天,造成大鼠吗啡依赖模型。（1）在末次注射吗啡后12小时,将大鼠随机分成4组,分别给予4次、2次、1次100Hz电针刺激（每次30min）,或不给电刺激作为对照。在末次注射吗啡24小时,观察并记录75分钟内的自然戒断症状。（2）测试自然戒断症状后,将这4组大鼠继续饲养7天后,用纳络酮（1mg/kg,i.p.)催瘾,观察记录30分钟内的戒断症状。结果：(1)4次电针刺激组抑制吗啡戒断症状的效果显著优于对照组（P＜0．01）、1次（P＜0．01）及2次（P＜0．05）电针组。（2）多次电针刺激后一周,仍可以看出电针刺激组钠络酮诱发的戒断症状均显著少于对照组（P＜0．01）,且4次电针刺激组的效果显著优于1次组（P＜0．05）。结论：（1）4次电针刺激抑制自然戒断症状的作用优于单次,说明针效有累加作用。（2）多次（2－4次）电针刺激对戒断症状的抑制作用至少可维持一周。     

吗啡依赖与戒断大鼠脑组织μ阿片受体的变化

目的用光学放射自显影术对吗啡依赖与戒断大鼠脑组织μ阿片受体进行定位和定量研究.方法30只SD大鼠随机分为吗啡依赖组、吗啡戒断组和生理盐水对照组,每组10只.依赖组和戒断组大鼠以腹腔注射吗啡的方法建立吗啡依赖模型,戒断组在依赖后腹腔注射纳洛酮5 mg/kg诱导戒断症状,对照组注射生理盐水.取大鼠不同脑区(包括额叶皮质、海马、纹状体、丘脑、下丘脑)进行光学放射自显影研究,分析大鼠依赖及戒断前后μ阿片受体数目及分布的改变.结果(1)依赖组大鼠与对照组大鼠相比,额叶皮质、海马、纹状体、丘脑、下丘脑的μ受体特异性结合密度发生非常显著下降(P＜0.01);(2)戒断组大鼠与吗啡依赖组比较,额叶皮质、丘脑、海马、纹状体、下丘脑的μ受体特异性结合密度发生了显著的上调(P＜0.05或0.01).但除下丘脑外(P＞0.05),其余脑区的μ受体特异性结合密度仍非常显著地低于正常水平(P＜0.01).结论实验结果表明大鼠不同脑区在吗啡依赖过程中μ阿片受体出现明显下调,予纳洛酮催促戒断,μ阿片受体较依赖组大鼠有显著回升,但仍显著低于正常组水平,这可能是阿片类依赖和戒断的重要神经生物学机制之一.     

石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用

目的：观察石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用。方法：采用连续递增皮下注射吗啡,建立吗啡依赖动物模型;给石菖蒲实验组大鼠不同剂量（2.5 g/kg、5 g/kg、7.5 g/kg）的石菖蒲水煎剂灌胃后,用纳络酮催瘾（0.5 mg/kg）,观察每组大鼠戒断反应中出现的咬牙、湿狗样抖动、扭体等六种戒断症状,评价大鼠戒断反应的强度。结果：与盐水对照组比较,石菖蒲水煎剂对吗啡依赖大鼠的戒断症状均有不同程度的抑制作用,其中以5 g/kg剂量组的作用最为突出（P〈0.01）。结论：石菖蒲水煎剂能明显抑制吗啡依赖大鼠的戒断症状。     

和厚朴酚与厚朴酚在缓解大鼠吗啡戒断反应中对β-内啡肽的影响

背景现代药理证实和厚朴酚与厚朴酚具有中枢抑制作用和肌肉松弛作用,且有报道证实其可缓解动物吗啡依赖戒断症状.目的探讨和厚朴酚与厚朴酚在缓解吗啡戒断反应中对β-内啡肽的影响.设计随机对照实验.单位湖北民族学院医学院药理学教研室.对象实验于2003-04-13/29进行,取成年雄性SD大鼠100只,其中30只大鼠作为对照组随机分成生理盐水组、和厚朴酚组和厚朴酚组各10只,另外70只大鼠作为吗啡依赖组,随机分成生理盐水组,和厚朴酚5,40,80mg/kg组与厚朴酚5,40,80 mg/kg组7组,各10只.方法对照组中3个亚组分别腹腔注射生理盐水0.2 mL、和厚朴酚与厚朴酚各80 mg/kg.吗啡依赖组大鼠逐日增量皮下注射吗啡6 d,建立急性吗啡依赖大鼠及吗啡自然戒断模型,在第6天900最后一次给吗啡后,1030腹腔注射给药,生理盐水组给予生理盐水0.2 mL,其他6组分别给予和厚朴酚、厚朴酚各5,40和80 mg/kg.于1100分别观察吗啡依赖组每只大鼠1 h内各项自然戒断症状.主要观察指标①各组大鼠脑脊液中β-内啡肽水平.②比较吗啡依赖组中7个亚组大鼠自然戒断症状评分.结果①脑脊液中β-内啡肽水平对照组中和厚朴酚与厚朴酚组显著高于生理盐水组(P＜0.01),而且和厚朴酚强于厚朴酚(P＜0.05).吗啡依赖+生理盐水组明显低于对照+生理盐水组(P＜0.01).吗啡依赖组中和厚朴酚与厚朴酚5,40,80 mg/kg组均高于生理盐水组(P＜0.01),而且呈量效关系.②吗啡依赖组大鼠自然戒断症状评分和厚朴酚与厚朴酚各剂量组湿狗样抖动、舔阴,逃避症状得分均低于生理盐水组(P＜0.05,0.01),且剂量越大效果越显著;和厚朴酚与厚朴酚40,80 mg/kg组咬牙、扭体及体质量丢失显著低于生理盐水组(P＜0.01).结论和厚朴酚与厚朴酚可明显抑制吗啡戒断反应,且抑制效应呈量效关系,这一抑制效应与脑内β-内啡肽的增加有关.这种效应对吗啡依赖大鼠和厚朴酚与厚朴酚相当,对正常大鼠和厚朴酚强于厚朴酚.     

吗啡依赖与戒断大鼠脑组织μ阿片受体的变化

背景内源性阿片肽-阿片受体系统的改变是阿片类药物成瘾的一个重要机制.在离体条件下,给予μ阿片受体拮抗剂或激动剂可以调节阿片受体水平.但不同的实验结果差别很大.目的用光学放射自显影术对吗啡依赖与戒断大鼠脑组织μ阿片受体进行定位和定量研究.设计完全随机分组实验研究.地点和对象实验在第二军医大学长征医院麻醉科完成,对象为雄性SD大鼠30只,体质量180～220 g,由第二军医大学动物实验中心提供.干预30只SD大鼠随机分为吗啡依赖组、吗啡戒断组和生理盐水对照组,每组10只.依赖组和戒断组大鼠以腹腔注射吗啡的方法建立吗啡依赖模型,戒断组在成瘾后腹腔注射纳洛酮5 mg/kg诱导戒断24 h,对照组注射生理盐水.主要观察指标大鼠不同脑区μ阿片受体特异性结合密度.结果依赖组大鼠与对照组大鼠相比,额叶皮质、海马、纹状体、丘脑、下丘脑的μ受体特异性结合密度发生非常显著下降(t=11.54,17.82,15.80,8.35,13.78,P＜0.01),下降幅度分别为22%,49%,21%,28%,39%;戒断组大鼠与吗啡依赖组比较,额叶皮质、海马、纹状体、丘脑、下丘脑的μ受体特异性结合密度发生了显著的上调(t=3.72,7.77,5.84,3.06,11.24,P＜0.01),上调幅度分别为10%,38%,12%,13%,58%.但除下丘脑外(t=1.64,P＞0.05),其余脑区的μ受体特异性结合密度仍非常显著地低于正常水平(t=6.76,11.73,10.19,5.46,P＜0.01).结论大鼠不同脑区在吗啡成瘾过程中μ阿片受体出现明显下调,予纳洛酮催促戒断,μ阿片受体较依赖组大鼠有显著回升,但仍显著低于正常组水平,这可能是阿片类依赖和戒断的重要神经生物学机制之一.     

100Hz电针促进吗啡依赖和戒断大鼠脊髓强啡肽的释放

目的：研究在吗啡依赖和戒断大鼠１００ＨＺ电针是否仍有镇痛作用。该作用是否仍由脊髓强啡肽通过ｋ受体介导。方法：测定辐射热甩尾阈（ＴＦＬ）作为痛阈。结果：（１）给大鼠皮下注射递增量吗啡８天造成大鼠对吗啡的依赖。这时给以１００ＨＺ电针，ＴＦＬ仍有显著升高，此作用可被大剂量纳洛酮翻转，提示由ｋ阿片受体介导；（２）吗啡依赖和或断大鼠脊髓灌注液中强腓肽放免活性明显降低，１００ＨＺ电针使之显著回升。结论：在大鼠     

盐酸纳洛酮在急诊和急性中毒的应用

盐酸纳洛酮(Naloxone hydrochliride,商品名Narcan,NX),为羟二氢吗啡酮的衍生物。是阿片受体(opiate receptor)纯拮抗剂而无激动活性,与阿片受体的亲和力大于吗啡和脑啡肽,能竞争性地阻止并取代阿片样物质与受体的结合,解除阿片类药物中毒症状,并能迅速诱发阿片成瘾者的戒断症状。1961年Blumderg报道,纳洛酮能拮抗羟二氢吗啡酮引起的小鼠镇痛与致死以及家兔的呼吸抑制作用,较烯丙吗啡(Nalorphine)强7～10倍,其结构与吗啡极为相似。仅在N-以烯丙基取代甲基,6位羟基变为酮基,结构式如下:     

三叶委陵菜乙醇提取物镇痛作用的研究

目的研究三叶委陵菜乙醇提取物的镇痛作用.方法热板法和扭体法.结果热板法中,灌胃三叶委陵菜乙醇提取物(0.5 g/kg,1.25g/kg,2.5g/kg)15,30,60和90min后,小鼠的痛阈均明显延长,其中灌胃2.5g/kg提取物90min后的镇痛效应比氨基比林(100 mg/kg i.m.)的好.在对非甾体药敏感的扭体法中,不同剂量的三叶委陵菜醇提物(0.5 g/kg,1.25g/kg,2.5g/kg o.p.)均能显著抑制0.7%醋酸引起的扭体反应.结论三叶委陵菜具有镇痛效应,民间用三叶委陵菜医治牙痛及其它疼痛症的疗效得到了验证.     

N-乙酰-5-甲氧色胺镇痛作用的实验研究

目的为了寻找新型镇痛药物,对N-乙酰-5-甲氧色胺(Mel)的镇痛作用及其与哌替啶(Pt)的协同作用进行探索性研究。方法采用小鼠热板法及冰乙酸致小鼠扭体为疼痛模型,观察Mel对痛阈的影响。结果Mel30,60,120mg/kg剂量依赖性地增加小鼠痛阈,且于给药后1h达高峰,持续至2h仍有效。此外,无镇痛效应的Mel(10mg/kg)与哌替啶(10mg/kg)合用,能明显提高小鼠痛阈。结论Mel具有良好的镇痛作用,增大剂量完全能达到哌替啶的镇痛效应,且与哌替啶有明显协同效应。     

孤啡肽基因敲除小鼠电针镇痛作用增强

目的：孤啡肽是阿片受体样受体（ORL1）的内源性配基,蛇能调节疼痛与镇痛反应以及针刺镇痛反应,但各个实验室所得结果各不相同。本文利用OFQ基因敲除的小鼠为工具,观察内源性OFQ在针刺镇痛中的作用。方法：采用本实验室建立的小鼠电针方法,选用穴位足三里（SP36）与三阴交（SP6）,电针参数采用韩氏仪恒流方波输出,强度1.0-1.2-1.4 mA,每10min递增一级。痛阈的改变以热辐射甩尾来评价。结果：与野生型小鼠相比,OFQ基因高除小鼠基础痛阈明显延长,对100Hz电针镇痛反应显著增强,但不影响2Hz电针镇痛。结论：在整体情况下,内源性OFQ有紧张性的致痛敏作用,并对100Hz针刺镇痛有拮抗作用。     

小鼠低频和高频电针镇痛阿片机制的探讨

探讨小鼠低频和高频电针镇痛的阿片机制。方法：采用交叉耐受和受体药理学方法,以甩尾潜伏期增加的百发数作为评判电针镇痛效果的指标。结果：（１）吗啡镇痛与２Ｈｚ电针镇痛之间存在交叉耐受。（２）２／１００Ｈｚ电针镇痛分别与２Ｈｚ、１００Ｈｚ电针镇痛存在交叉耐受;而２Ｈｚ电针镇痛与１００Ｈｚ电针镇痛不存在交叉耐受。（３）ＣＣＫ受体拮抗剂Ｌ３６５,２６０可显著加强１００Ｈｚ电针镇痛效应,对２Ｈｚ电针镇痛无明显     

100Hz电针和脊髓鞘内注射强啡肽A引起大鼠镇痛作用的性别差异

目的：比较１００Ｈｚ电针对雌性与雄性大鼠的镇痛作用,以及脊髓蛛网膜下腔（ｉ．ｔ．）注射阿片κ受体激动剂强啡肽Ａ１１７（ＤｙｎＡ）对雌、雄大鼠镇痛的差异性。方法：用辐射热甩尾法测痛。为避免强啡肽的致瘫作用,本实验采用小剂量（５μｇ或２．３ｎｍｏｌ,１０μｌ）ｉ．ｔ．注射,并以斜板试验观察大鼠运动功能的变化。结果：雌性大鼠１００Ｈｚ电针的镇痛作用强于雄性大鼠,这种差异以电针２０ｍｉｎ时最为显著。ｉ．ｔ．注射ＤｙｎＡ２．３ｎｍｏｌ后１０ｍｉｎ雌鼠有镇痛作用,而雄鼠在给药后６０ｍｉｎ内均未表现镇痛作用。结论：１００Ｈｚ电针对雌性大鼠的镇痛作用强于雄性,这种性别差异可能与脊髓水平强啡肽镇痛的性别差异有关。     

Intravenous bolus of ultra-low-dose naloxone added to morphine does not enhance analgesia in emergency department patients.

There is some evidence from in vitro, animal, and postoperative clinical studies that low doses of opioid antagonists combined with morphine increase analgesia. The theoretical model of this effect posits that ultra-low doses of opioid antagonists selectively antagonize excitatory, but not inhibitory, opioid receptor-mediated signaling. To determine whether this effect occurs in emergency department patients presenting with severe acute pain, we conducted a randomized, double-blind placebo-controlled trial to assess the relative analgesic effect of morphine administered with 3 different doses of naloxone versus morphine alone. Patients received 0.1 mg/kg morphine intravenously (IV) over 2 min plus one of 3 different doses of naloxone (0.1 ng/kg, 0.01 ng/kg, or 0.001 ng/kg) or normal saline. A 0 to 10 numerical rating scale (NRS) was used to measure pain intensity at baseline and every 30 min up to 4 hours. One hundred fifty-six patients with a median NRS of 10 (IQR: 8-10) were studied. There were no clinically or statistically significant differences in the mean pain intensity of patients in the 4 treatment groups over the 4-hour study period, nor were there differences in the administration of additional analgesics or incidence of side effects. PERSPECTIVE: Ultra-low doses of naloxone in the 0.001 ng/kg to 0.1 ng/kg range do not enhance the analgesia provided by morphine alone among emergency department patients with acute, severe pain. This suggests that naloxone in these doses is not an effective adjunct to morphine for control of acute pain.     

A minimal stress model for the assessment of electroacupuncture analgesia in rats under halothane.

The use of anesthetics in acupuncture analgesia is controversial. We evaluate a steady-state light anesthesia model to test whether minimal stress manipulation and reliable measurement of analgesia could be simultaneously achieved during electroacupuncture (EA) in animals. A series of experiments were performed. Firstly, EA compliance and tail-flick latencies (TFL) were compared in rats under 0.1%, 0.3%, 0.5%, 0.7%, or 1.1% halothane for 120min. Under 0.5% halothane, TFL were then measured in groups receiving EA at intensity of 3, 10 or 20 volt (V), 1 or 2mg/kg morphine, 20V EA plus naloxone, or control. Subsequently, the effect of EA on formalin-induced hyperalgesia was tested and c-fos expression in the spinal dorsal horn was analyzed. Rats exhibited profound irritable behaviors and highly variable TFL under 0.1% or 0.3% halothane, as well as a time-dependent increase of TFL under 0.7% or 1.1% halothane. TFL remained constant at 0.5% halothane, and needle insertion and electrical stimulation were well tolerated. Under 0.5% halothane, EA increased TFL and suppressed formalin-induced hyperalgesia in an intensity-dependent and naloxone-reversible manner. EA of 20V prolonged TFL by 74%, suppressed formalin-induced hyperalgesia by 32.6% and decreased c-fos expression by 29.7% at the superficial and deep dorsal horn with statistically significant difference. In conclusion, 0.5% halothane provides a steady-state anesthetic level which enables the humane application of EA stimulus with the least interference on analgesic assessment. This condition serves as a minimal stress EA model in animals devoid of stress-induced analgesia while maintaining physiological and biochemical response in the experiment.     

Behavioural evidence that systemic morphine may modulate a phasic pain-related behaviour in a rat model of peripheral mononeuropathy.

In a model of peripheral mononeuropathy produced by 4 ligatures around the sciatic nerve, we investigated the effects of various i.v. doses of morphine on the vocalization thresholds elicited by paw pressure and compared the effects obtained with the same doses in normal rats. In neuropathic rats, morphine (0.1 and 0.3 mg/kg) produced a significant analgesic effect on the lesioned hind paw, maximum at 15 min post injection with a recovery at 20-25 min. For doses of 0.6 and 1 mg/kg, a modification of the kinetics was observed, with maximum effect at 20-30 min post injection and a recovery at 50-80 min. An analgesic effect was also observed on the unlesioned side, significantly less potent than that observed on the lesioned paw. The effect of 1 mg/kg morphine was almost totally reversed by a 0.1 mg/kg dose of systemic naloxone. The effects induced by the successive doses of morphine on the lesioned paw appeared higher than in normal rats (maximum vocalization thresholds (% of control) following 1 mg/kg morphine (N = 12) were 193.92 +/- 6.57% versus 154 +/- 3.5% in normal rats N = 3), whereas they were comparable to those obtained from the sham-operated paw. The present data clearly show that morphine induces potent antinociceptive effects in a rat model of neuropathy, which seems to contradict the classical view that neuropathic pain is opioid resistant. Some possible pathophysiological mechanisms are discussed.     

Interaction between opioid antagonists and amphetamine: evidence for mediation by central delta opioid receptors.

Naloxone, the opioid receptor antagonist, attenuates the effects of amphetamine in a wide range of behavioral paradigms. To determine the role of the opioid receptor subtypes in this phenomenon, subtype-selective opioid receptor antagonists were administered intracisternally to rats either as a 15-min [naloxone methiodide (NX.M) and naltrindole (NTI)] or a 24-hr [beta-funaltrexamine (beta-FNA) and norbinaltorphimine (nBNI)] pretreatment. Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.) with dosing every 30 min. Motor activity (gross and fine movements) was recorded for 20 min, commencing 10 min postinjection. Amphetamine dose-dependently increased both fine and gross movements. NX.M (30 micrograms) and NTI (10 and 30 micrograms) attenuated the gross activity response to amphetamine but did not alter the increase in fine movements. Lower doses of NX.M (2.0 and 10 micrograms) potentiated the fine activity response to amphetamine without any effect on the gross movements. Pretreatment with beta-FNA (1.25-20 micrograms), nBNI (10 and 30 micrograms) or NX.M (5.0 mg/kg s.c.) did not influence the response to amphetamine. However, beta-FNA and nBNI blocked the antinociceptive effects of morphine and spiradoline, respectively, indicating that these antagonists were tested under appropriate conditions for opioid receptor blockade. These data indicate a central site of action for the opioid antagonist-amphetamine interaction. The ability of NX.M (i.c.) and NTI, but not beta-FNA or nBNI, to influence the motor activity response to amphetamine implicates delta receptors in the opioid-mediated modulation of the behavioral stimulant effects of amphetamine.     

Potentiation of vancomycin-induced histamine release by muscle relaxants and morphine in rats

The intravenous injection of vancomycin sometimes causes anaphylactoid reactions, in which histamine release may play a major role. These reactions are more frequently manifested when vancomycin is injected into anesthetized patients. We examined the vancomycin-induced histamine release and the interaction of vancomycin with muscle relaxants or opioid in rats. In an in vitro study with rat peritoneal mast cells, treatment with vancomycin at concentrations of greater than 1.25 mM produced significant histamine release. Tubocurarine, vecuronium, pancuronium, succinylcholine, and morphine up to concentrations of 0.25, 1, 5, 30, and 5 mM, respectively, produced no significant histamine release. However, the nonsignificant histamine release induced by 0.5 mM vancomycin was clearly enhanced by combining vancomycin with any of these agents. In the in vivo study, the intravenous injection of vancomycin significantly increased the plasma histamine levels in rats when vancomycin was injected at 200 mg/kg of body weight (63.2 +/- 34.0 ng/ml [mean +/- standard deviation]) but not when it was injected at 100 mg/kg (30.8 +/- 20.2 ng/ml) compared with that in the saline-treated rats (22.5 +/- 11.4 ng/ml). Although the subcutaneous administration of morphine (10 mg/kg) never increased the plasma histamine levels, the intravenous injection of vancomycin (100 mg/kg) 30 min after this morphine treatment markedly increased the plasma histamine levels (56.0 +/- 26.9 ng/ml). These findings provide experimental evidence that the combination of muscle relaxants or an opioid with vancomycin may increase the risk of anaphylactoid reactions by enhancing the release of histamine.     

Clocinnamox: a novel, systemically-active, irreversible opioid antagonist.

The warm water (55 degrees C) tail-withdrawal procedure was used to assess the analgesic effects of the prototypic mu opioid agonists, morphine and fentanyl, in mice. Both drugs produced full analgesic effects under these conditions, which were dose-dependently antagonized by naltrexone. The pA2 values for naltrexone with morphine and with fentanyl were not significantly different. Low doses (e.g., 0.32 mg/kg) of clocinnamox [C-CAM.14 beta-(p- chlorocinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnormorphin one mesylate] produced rightward shifts in the dose-effect curves for each drug, whereas high doses (e.g., 32 mg/kg) depressed the maximal analgesic response. In addition, it was observed that higher doses of C-CAM were required to produce a shift down in the fentanyl dose-effect curve than were required to produce a shift down in the morphine dose-effect curve, which suggests that fentanyl is more efficacious than morphine. The highest dose of C-CAM (32 mg/kg) antagonized the analgesic effect of morphine for up to 8 days. In contrast, the antagonist activity of naltrexone (100 mg/kg) against morphine lasted for only 2 days. Finally, when naloxone was administered simultaneously with 32 mg/kg C-CAM 2 days before determination of the morphine dose-effect function, the antagonist effect of C-CAM was prevented in a dose-dependent manner. Taken together, these results suggest that C-CAM may be producing its antagonist action at opioid receptors through a nonequilibrium mechanism.