Footshock induced analgesia in mice: its reversal by naloxone and cross tolerance with morphine

Using the abdominal constriction response as the criterion for analgesia, mice tested immediately after a period of footshock showed a significant analgesic response compared with non-footshocked controls. Footshock induced analgesia could not be elicited in mice that had been made tolerant to morphine or in mice that had been pretreated with the narcotic antagonist naloxone. It is concluded that footshock induced analgesia in the mouse is due to the release of endogenous opioid peptides.     

Stereospecific reversal of nitrous oxide analgesia by naloxone

The opiate antagonist naloxone was found to block nitrous oxide analgesia in a stereospecific fashion. Using a modified hotplate test in mice, the (-)-enantiomer of naloxone (which has a KD of approximately 1 nM for opiate receptors) antagonized the analgesic actions of nitrous oxide in a dose-dependent (2.5-20 mg/kg) fashion. In contrast, the (+)-enantiomer (KD approximately 10,000 nM) had no effect on nitrous oxide analgesia at the highest dose tested (40 mg/kg). These data strongly suggest that nitrous oxide analgesia is mediated via opiate receptors and is consistent with the hypotheses that this effect occurs either through the release of endogenous opioids or by physical perturbation of the opiate receptors.     

Acupuncture analgesia in rats and its changes under the effect of morphine and naloxone

It was established in chronic experiments on rats that electric acupuncture of the acupuncture point noticeably decreases pain reaction to electric stimulation of the tail. Morphine given in a subanalgetic dose (5 mg/kg) potentiated acupuncture analgesia, while 5 mg/kg of naloxone completely abolished it. Potential mechanisms of analgesia realization during electric acupuncture are discussed.     

Differential effects on morphine analgesia and naloxone antagonism by biogenic amine modifiers.

The stimulation of dopaminergic receptors, inhibition of serotonin synthesis or blockade of muscurinic receptors by various modifiers led to inhibition of morphine analgesia in mice. Blockade of dopaminergic receptors or the increase in serotonergic or cholinergic activity resulted in the enhancement of morphine analgesia. Serotonergic and cholinergic systems are proposed as positive and the dopaminergic system as negative modulators of morphine analgesia. The modulation of naloxone antagonism was much more complicated than that of morphine analgesia and often the effect of biogenic amine-modifiers on antagonism differed from that on analgesia. The fact that biogenic amine-modifiers do not affect morphine analgesia and naloxone antagonism by a similar pattern suggest that interaction of narcotics and narcotic antagonists with analgesic receptors may not be exactly the same.     

Effect of naloxone on analgesia induced by food deprivation

Naloxone (4 mg/kg) or saline was administered to animals under food deprived and non-deprived conditions prior to testing pain sensitivity in the tail flick test. Food deprived animals exhibited significantly elevated latencies in comparison to latencies observed under non-deprived conditions. This analgesia was diminished by treatment with the opiate receptor antagonist, naloxone. These findings suggest that analgesia induced by food deprivation is mediated in part by opiate receptor systems.     

Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers

Effect of four calcium channel blockers (CCBs) belonging to different chemical classes, alone and in combination with morphine was investigated on two models of pain sensitivity, i.e. formalin and tail flick tests in mice. All the studied CCBs, i.e. diltiazem, flunarizine, nimodipine and verapamil inhibited formalin-induced pain responses; however, with verapamil, though there was a trend towards a reduction of paw-licking response to formalin, it was not found to be statistically significant. In contrast, none of the CCBs affected the tail flick latency at any of the doses studied. Morphine, a mu-receptor agonist exerted a significant analgesic effect in formalin as well in tail flick tests. Pretreatment with all CCBs significantly enhanced the analgesic effect of morphine in both tests of nociception. Further, concomitant administration of one of the CCBs, diltiazem with morphine prevented the development of tolerance to the latter. However, combination of diltiazem with morphine, like morphine alone was found to be ineffective in morphine tolerant animals. Results, thus, show that CCBs produced an analgesic effect of their own in formalin-induced tonic pain and potentiated the analgesic activity of morphine. They also modulated opioid-induced tolerance.     

Tolerance to morphine in the rat: its prevention by naloxone.

Development of tolerance after a single injection of morphine in the Wistar-Lewis rat can be estimated by the attenuation of the response to a second injection of morphine given three days later. If naloxone is given 35 minutes after the first morphine injection and after the appearance of measurable analgesia, attenuation of the effects of the second morphine injection is not seen. It appears that naloxone blocks the development of tolerance to morphine even if given after the morphine-receptor interaction responsible for analgesia has been initiated. The temporal relationship between the prior injection of morphine and the subsequent administration of naloxone is being explored.     

GABA involvement in naloxone induced reversal of respiratory paralysis produced by thiopental

No agent is yet available to reverse respiratory paralysis produced by CNS depressants, such as general anesthetics. In this study naloxone reversed respiratory paralysis induced by thiopental in rats. 25 mg/kg, i.v. thiopental produced anesthesia without altering respiratory rate, increased GABA, decreased glutamate, and had no effect on aspartate or glycine levels compared to controls in rat cortex and brain stem. Pretreatment of rats with thiosemicarbazide for 30 minutes abolished the anesthetic action as well as the respiratory depressant action of thiopental. 50 mg/kg, i.v. thiopental produced respiratory arrest with further increase in GABA and decrease in glutamate again in cortex and brain stem without affecting any of the amino acids studied in four regions of rat brain. Naloxone (2.5 mg/kg, i.v.) reversed respiratory paralysis, glutamate and GABA levels to control values in brain stem and cortex with no changes in caudate or cerebellum. These data suggest naloxone reverses respiratory paralysis produced by thiopental and involves GABA in its action.     

Influence of air ions on brain activity induced by electrical stimulation in the rat

The brain induced activity was studied in 18 rats wearing chronically skull implanted electrodes. The stimulating factor was various electrical stimulations of the mesencephalic reticular activating formation, given during the slow wave state of sleep. The results of 300 stimulations were measured by amplitude and frequency changes in the EEG simultaneously recorded. Animals previously exposed to positive air ions (3 weeks 80,000 ions/ml) exhibited lowered excitability of the reticulocortical system. Significantly higher stimulations were necessary to induce arousal. Negative air ions induced more intricate effects: brain excitability was lowered when tested with weak stimulations, but normal when evaluated with medium high level stimilations. Sleep seems first more stable but as stimulation increases, arousal is soon as effective as in controls. These results are in agreement with others findings in behavioral fields and partly explains them.     

Changes in morphine self-administration in rats induced by prostaglandin E1 and naloxone

Interactions of prostaglandin E₁ (PGE₁) with morphine have been reported in several test systems and an hypothesis has been advanced for a role of prostaglandins in morphine analgesia and physical dependence. In rats self-administering morphine intravenously, a simultaneous and continuous infusion of naloxone hydrochloride at 56 to 560 μg/kg/day caused the expected increase in injection rate for morphine. Infusion of PGE₁ by itself at 56 or 180 μg/kg/day had no effect on the rate of morphine intake. Likewise the addition of PGE₁ at 180 μg/kg/day did not potentiate the increase caused by naloxone (56 or 180 μg/kg/day) when it was added to the naloxone infusion. These results do not support a role for prostaglandins in the behavioral aspects of morphine addiction. However, larger doses of PGE₁ (1 and 1.8 mg/kg/day), which were without overt effects in normal rats, caused severe and incapacitating prostration in morphinized rats.     

Trans-cranial electrical stimulation attenuates the severity of naloxone-precipitated morphine withdrawal in rats

The expression of morphine withdrawal in rats has been demonstrated as dependent upon the integrity of specific brain regions. Focal intracranial electrical stimulation of some of these sites results in the attenuation of withdrawal severity. The present study demonstrates that electrical auricular stimulation, in a paradigm known to attenuate nociceptive responses of several brain nuclei, attenuates the severity of naloxone-precipitated morphine withdrawal in rats. This simple non-invasive treatment, based on long-standing principles of electroacupuncture, may provide a useful adjunct for therapy of the narcotic withdrawal syndrome.     

Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide

Opioid overdose, which is commonly associated with opioid induced respiratory depression, is a problem with both therapeutic and illicit opioid use. While the central mechanisms involved in the effects of opioids are well described, it has also been suggested that a peripheral component may contribute to the effects observed. This study aimed to further characterise the effects of the peripherally acting naloxone methiodide on the respiratory, analgesic and withdrawal effects produced by various opioid agonists. A comparison of the respiratory and analgesic effects of morphine, methadone and heroin in male Swiss-Albino mice was conducted and respiratory depressive ED(80) doses of each opioid determined. These doses (morphine 9 mg/kg i.p., methadone 7 mg/kg i.p., and heroin 17 mg/kg i.p.) were then used to show that both naloxone (3 mg/kg i.p.) and naloxone methiodide (30-100 mg/kg i.p.) could reverse the respiratory and analgesic effects of these opioid agonists, but only naloxone precipitated withdrawal. Further investigation in female C57BL/6J mice using barometric plethysmography found that both opioid antagonists could reverse methadone induced decreases in respiratory rate and increases in tidal volume. Its effects do not appear to be strain or sex dependent. It was concluded that naloxone methiodide can reverse the respiratory and analgesic actions of a variety of opioid agonists, without inducing opioid withdrawal.     

Cortical spreading depression synaptically induced by brief high-frequency electrical stimulation of the rat brain

Electrical stimulation (ES) at the surface of the rat brain (10–200 Hz; brief trains of 10 pulses) was found to be most effective for evoking waves of spreading depression (SD) in the cortex. Repeated stimuli spaced at 10–15 min intervals did not produce convulsive activity and nor did mechanisms of SD inhibition set in under these conditions. A 5–6-fold reduction in SD threshold occurred when the intra-burst rate was increased from 10 to 200 Hz. Temporal summation of residual processes occurring with suprathreshold ES applied at the rate of 50 and 200 Hz resulted in significant broadening of the SD focus in the ES area and regular occurrence of additional SD foci on the side ipsilateral to stimulation and in the contralateral cortex. The protracted changes in cortical excitation lingering after ES by high-frequency currents brought about a decline in SD threshold and pointed to the active part played by synaptic processes in triggering this reaction.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 21, No. 6, pp. 789–796, November–December, 1989.     

吗啡和纳洛酮对酸化十二指肠引起狗胰液分泌的影响

本工作用制备 Thomas 胰瘘和胃痿的5条狗进行慢性实验。实验时用0.1N 盐酸灌入十二指肠以刺激胰液分泌,并分別注射吗啡或/和纳洛酮,观察它们对胰液分泌和对胰液中碳酸氢盐和蛋白质浓度的影响。另外我们还观察了吗啡和纳洛酮对6条狗离体胰主导管紧张性的影响。结果表明:(1)吗啡抑制了胰液分泌量,对胰液中碳酸氢盐和蛋白质浓度无影响,由于分泌量减少故两者的排出量显著减少(P<0.05),(2)纳洛酮本身对胰液分泌量和碳酸氢盐及蛋白质浓度均无影响;(3)纳洛酮可以加强吗啡抑制胰液分泌的作用(P<0.01);(4)吗啡能增加狗的离体胰主导管肌条的紧张性,纳洛酮不能阻断或翻转吗啡的这一效应,相反能加强其效应。本工作表明,吗啡抑制酸化十二指肠所引起的胰碳酸氢盐和蛋白质排出量,其机制可能是吗啡刺激胰导管收缩,而纳洛酮则加强吗啡的这种抑制效应。     

Failure of naloxone to influence surgical reversal of two-kidney, one-clip hypertension in the rat

The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (less than 6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either unclipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the unclipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.     

Naloxone reversal of morphine analgesia but failure to alter reactivity to pain in the formalin test.

Rats treated with naloxone in doses sufficient (10 mg/kg) to completely antagonize morphine analgesia showed no decrease in their thresholds of reactivity to formalin-induced chronic pain. These findings fail to support the hypothesis that tonic release of endogenous opioids acting at naloxone-sensitive receptors decreases sensitivity or reactivity to pain stimuli.     

The effects of naloxone on the changes in breathing and behaviour induced by morphine in the foetal sheep

In the foetal sheep, administration of morphine induces apnoea followed by hyperpnoea; during hyperpnoea the foetus arouses. We tested the hypothesis that naloxone, an opiate antagonist, would block these responses. In 14 foetal sheep between 123 and 140 days of gestation, we measured electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (EMGdi), blood pressure and amniotic pressure. Morphine (1 mg/kg) was injected in the foetal jugular vein during low-voltage ECoG. Saline or naloxone (0.1, 0.5 and 2.0 mg) were given, in randomized order, before the morphine injection, shortly after morphine injection during apnoea, and during maximum hyperpnoea. Saline alone had no effect on breathing or behaviour. When saline and naloxone preceded the morphine injection the length of apnoea was 26.6 +/- 7.7 and 19.5 +/- 7.0 min (SEM, P = 0.25) while the length of sustained hyperpnoea was 104.8 +/- 11.4 and 29.6 +/- 8.4 min respectively (P = 0.001). When administered during the maximum breathing response, naloxone decreased the length of breathing from 92.2 +/- 8.4 (saline) to 8.8 +/- 2.9 min (P = 0.001). Respiratory output (fEMGdi x f) also decreased from 6545 +/- 912 arbitrary units post saline to 3841 +/- 629 arbitrary units after naloxone (P = 0.05). Arousal disappeared with the decrease in breathing response. The negligible effect of naloxone on apnoea and its strong inhibition of hyperpnoea suggest that morphine may act on two distinct central regions or on two subtypes of opioid receptors to produce apnoea, hyperpnoea and arousal.     

化学刺激或电刺激大鼠穹窿下器官诱发的饮水行为和脑内c-fos表达

目的对化学刺激和电刺激穹窿下器官(subfornical organ, SFO)诱发的饮水量和脑内c-fos表达的结果是否不同进行比较. 方法向大鼠SFO内微量注射L-谷氨酸作为化学刺激,用恒流刺激SFO作为电刺激,记录诱发的1 h内饮水量,用免疫组化方法检测脑内Fos蛋白表达.结果电刺激和化学刺激SFO均能诱导相似的饮水行为,其诱饮率分别为75%和85.7%,1 h平均饮水量分别为(0.28±0.22) ml 和(0.31±0.15) ml ,明显高于各自的对照组(P<0.05),并均能使前脑的 11个脑区(终板血管器官, 正中视前核,室旁核,视上核,下丘脑外侧区,丘脑室旁核,联合核和中央内侧核,终纹床核,穹窿周背区和无名质)和后脑的4个脑区(最后区,孤束核,臂旁外侧核和中缝背核)相似的Fos蛋白表达.结论刺激SFO所诱导的饮水行为和脑内Fos蛋白表达是激活其神经元胞体的结果.     

Spinal analgesia: Comparison of the mu agonist morphine and the kappa agonist ethylketazocine

The sites of analgesic action of the mu agonist morphine and the purported kappa agonist ethylketazocine (EKC) were compared. Using local drug injections and parenteral administration of drugs to spinalized rats, our data support a predominantly spinal site of action for EKC and a major supraspinal action for morphine in antinociceptive tests. This spinal analgesic action of EKC was dose dependent and naloxone reversible indicating opiate receptor involvement. The possibility that EKC activates a spinal kappa receptor population is under further study.