Agonistic behaviour in rats: evidence for non-involvement of opioid mechanisms

It has recently been proposed that a stress-activated, endogenous analgesia mechanism would be adaptive in situations in which pain perception might otherwise disrupt effective behavioural performance. In a semi-natural test situation, the current study examined two predictions arising from this hypothesis: (1) in a manner analogous to other stressors, agonistic experience should produce analgesia and, if naloxone-sensitive opioid mechanisms are implicated, then (2) pretreatment with naloxone should block the development of this response and alter the displayed behaviour patterns. Neither prediction was substantiated by the data. Experience of an agonistic encounter failed to produce analgesia in either resident or intruder animals. Furthermore, naloxone hydrochloride (1-25 mg/kg) was also without effect on patterns of offense or defense. Data are discussed in relation to the critical nature of the stimulus factors involved in the activation of endogenous analgesic mechanisms and the postulated involvement of such mechanisms in biologically-adaptive behaviours.     

Naloxone injections into the periaqueductal grey area and arcuate nucleus block analgesia in defeated mice

In a situation of social conflict, mice that are defeated by an opponent exhibit a marked analgesia. Microinjections of naloxone (1 or 10 g) into the periaqueductal grey area (PAG) or into the region of the arcuate nucleus prior to the defeat prevented the emergence of analgesia. Microinjections of morphine (5 g) into these sites had previously been shown to produce profound analgesia. Mice whose adrenals were removed rapidly developed analgesia when attacked by a stimulus animal. Injection of naloxone into PAG also antagonized defeat-induced analgesia in adrenalectomized mice. These observations indicate that sites and processes in the brain rather than in the periphery are responsible for the development of analgesia in mice that are subjected to social defeat.     

Sensitivity of pulmonary chemo reflexes and lung inflation reflexes to repetitive stimulation and to inhibition with lidocaine and morphine

Summary To study reflex responses caused by stimulation of pulmonary C-fibers and lung inflation, we used a preparation in which the left pulmonary artery and veins were ligated and cannulated and the right and left bronchi were cannulated separately in open-chest dogs. These experiments were performed to establish whether the reflex responses to injections of 150 g of capsaicin through the left pulmonary circulation and inflations of this left lung to 30 cm H₂O would be diminished if repeated frequently. Furthermore, the sensitivities of the reflex responses evoked by these capsaicin injections and by left lung inflations (LLI) to blockade with lidocaine or with morphine were studied. Both repeated injections of capsaicin into the left pulmonary circulation and repeated inflations of the left lung for up to 100 min produced a persistent triad of reflex responses: bradycardia, hypotension, and cessation of diaphragmatic contractions. Lidocaine injections (50 mg) into the pulmonary artery of the vascularly isolated lung abolished all reflex responses to subsequent injections of capsaicin, but only attenuated the triad of responses to subsequent left lung inflations by half. Morphine sulfate (60 mg) administered to the pulmonary vascular bed of the isolated lung reduced, but did not eliminate, the triad of reflex responses to subsequent capsaicin injections and lung inflations. The influences of morphine upon capsaicin and lung inflation responses were not abolished by naloxone. These results indicate: (a) the sensory fibers which initiate the triad of pulmonary depressor reflex responses are not desensitized by repeated exposure to capsaicin or by repeated lung inflations; (b) sensory fibers other than pulmonary C-fiber receptors contribute to the lung inflation reflex; and (c) morphine and lidocaine interfere with the excitation of pulmonary C-fibers.     

Effects of low-level microwave irradiation on amphetamine hyperthermia are blockable by naloxone and classically conditionable

In a series of experiments, we investigated the effects of pulsed low-level microwave irradiation on amphetamine-induced hyperthermia in the rat. Rats were irradiated in a 2,450-MHz cylindrical waveguide exposure system at 1 mW/cm², 2 s pulses, 500 pps, average SAR of 0.6 W/kg. Acute (45 min) exposure to microwaves attenuated amphetamine-induced hyperthermia. This effect was blocked by pretreatment of the animals with the narcotic antagonist naloxone. In another experiment, rats were subjected to ten daily sessions of microwave exposure (45 min/session). On day 11, amphetamine-induced hyperthermia was studied in the animals immediately after a session of either microwave or sham exposure. Similar to the acute effect, amphetamine-induced hyperthermia was attenuated in rats irradiated with microwaves (unconditioned effect). In the sham-irradiated animals we observed a potentiation of the amphetamine-induced hyperthermia, which was a conditioned effect of microwaves. Thus, the conditioned effect (potentiation) was opposite in direction to the unconditioned effect (attenuation). No tolerance developed to the unconditioned effect after subchronic exposure. Furthermore, both conditioned and unconditioned effects of microwaves on amphetamine-induced hyperthermia could be blocked by treatment with naloxone. These data suggest that (1) microwave irradiation may activate endogenous opioids, which in turn alter the actions of psychoactive drugs, and (2) the effect of microwaves on drug action can be classically conditioned. Offprint requests to: H. Lai     

纳洛酮抢救海洛因中毒618例临床分析

目的：观察纳洛酮抢救海洛因中毒的疗效。方法：对618例海洛因中毒患,用纳洛酮抢救,首次剂量给纳洛酮针剂0．4－0．8mg静注,然后以0．4mg每5min1次,直到患清醒后再给0．8－1．2mg维持静滴。结果：618例中死亡9例,抢救成功率达98％。结论：纳洛酮是抢救海洛因中毒的理想特效药。     

Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone

  Rationale: Non-dependent and dependent opiate users appear to be driven by two distinct motivational factors: the primary reinforcing properties of the drug, and the negative reinforcing effects associated with relieving the negative affective component of opiate withdrawal in the dependent state. Objective: To investigate the motivational significance of opioid dependence on heroin self-administration (HSA) in rodents. Methods: Rats were trained to self-administer heroin intravenously (0.06 mg/kg per infusion; FR1), and opiate dependence was induced by subcutaneous implantation of two morphine (75 mg base) pellets.Rats in a non-dependent control group received placebo pellets. Three days after pellet implantation, HSA was resumed in daily 3-h sessions until baseline criteria were met and testing was conducted with subcutaneous injections of vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session. Results: Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet-implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a second experiment, the HSA session was shortened to 1 h and the training dose reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo pellet-implanted rats was increased only following the highest dose of the antagonist, while dependent rats were still affected by naloxone doses of 0.003–0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3), breaking point values in dependent animals were 198% above baseline. Conclusions: The present study supports the hypothesis that dependence-induction by morphine-pellet implant in rats resulted in increased sensitivity to very small naloxone doses, as measured by changes in HSA. Taken together, these data suggest that opiate dependence, as measured by changes in sensitivity to naloxone, is a continuum which can contribute to the motivational state of drug-seeking. Received: 5 June 1998 / Final version: 21 December 1998     

An electromyographic method for the assessment of naloxone-induced abstinence in morphine-dependent rats

Summary The electromyographic (EMG) activities of suprahyoideal muscle were recorded to measure naloxone-precipitated abstinence signs in morphine-dependent rats anesthetized with urethane (1 g/kg). Rats were rendered dependent on morphine by implanting 2 morphine pellets (75 mg each) and abstinence signs were induced by intravenous injections of various doses of naloxone at different times after pellet implantation. Three precipitated abstinence signs, a) myoclonic twitch activity (MTA), b) mastication, and c) body shakes were observed on EMG recordings after the injection of naloxone. Of these symptoms, only the MTA induced by naloxone (10 g/kg) occurred 4 h after pellet implantation and its sensitivity to naloxone increased with prolonged pellet implantation. Both mastication and precipitated shakes could be induced at 24 h. However, higher doses of naloxone were required to produce the shakes than is required to induce mastication. There appears to be a positive correlation between the intensity of naloxone-induced MTA and the degree of physical dependence on morphine. Since the MTA and mastication can be induced by low doses of naloxone in morphine-dependent rats, we suggest that these two parameters may be used to detect morphine abstinence signs in this species.Deceased February 13, 1979     

High-dose naloxone affects task performance in normal subjects

Increasing intravenous doses of naloxone (0.3 mg/kg, 1 mg/kg, and 2 mg/kg) were administered to normal subjects. Naloxone at 2 mg/kg, but not at lower doses, impaired aspects of memory as measured by a verbal learning task which assessed the direct free recall and recognition of presented versus non-presented words of a single category (effortful processing) and the monitoring of the frequency of such presentations (automatic processing). At the same time "working" memory was left unaffected. The results suggest a role for the opioid system in some memory processes in man.     

Nonspecific excitatory effects of morphine: Reverse-order precipitated withdrawal and dose-dose interactions

We recently reported that, in naive mice pretreated with naloxone, morphine can cause withdrawal-like signs that seemingly are not mediated by opiate receptors. Such results were confirmed and extended here with another mouse strain. Repetitive vertical jumping could occur irrespective of injection sequence and depended on dose and dose ratio of the two drugs.     

Précipitation et prévention de l'abstinence chez le rat et la souris en état de dépendance aiguë. Comparaison de la naloxone,de la naltrexone et de la diprenorphine

Summary Abstinence signs were precipitated in rats by naloxone (1 mg·kg^-1 s.c.) injected at various times (from 1.5 to 16 h) after a single dose of morphine hydrochloride (15 or 50 mg·kg^-1 s.c.) administered incaqueous solution. Increasing the dose of morphine increased the latency of the phenomena and the duration of the underlying state shifts of signs as described by Bläsig et al. (1974) in chronically morphinized rats also occurred when increasing the dose of morphine and the time interval between the injections of morphine and of naloxone. Naltrexone and diprenorphine were also effective. These three antagonists, given before morphine, were able to prevent precipitated abstinence: however, naloxone was almost ineffective when the higher dose of morphine was used and when the time interval was long. In these latter conditions, naltrexone was definitely more effective and longer acting and diprenorphine still more so. The same characteristics were found for the protective action of the three antagonists in acutely morphinized mice and the same order for their potencies in precipitating abstinence in acutely morphinized mice. Like naloxone, naltrexone and diprenorphine facilitated a nociceptive reaction in normal mice.The abstinence signs precipitated in acutely morphinized rats or mice are probably not unmasked excitatory effects of morphine as such effects should have been increased rather than inhibited by previous administration of specific antagonists; they might correspond to potentiated effects of the antagonists themselves. The prevention by specific antagonists of the abstinence syndrome is most simply interpreted by antagonism (direct or indirect) of dependence induction, but other interpretations are not excluded.