Histological studies were carried out on the degranulation of mesenteric mast cells of white rats caused by injections of morphine and nalorphine hydrochloride intravenously and the following conclusions were obtained. 1. By the injection of morphine hydrochloride fairly significant degranulation of the mesenteric mast cell was observed. 2. In various experimental doses of morphine hydrochloride the cytological change of the degranulation was not proportional to the doses of it in cases given more than 12mg./kg. of body weight. 3. The degranulating effect of the mesenteric mast cell by the injection of morphine hydrochloride was significantly inhibited by an adrenalectomy.
Adrenalectomy ; Animal ; Male ; Mast Cells/drug effects* ; Mesentery/drug effects* ; Morphine/antagonists & inhibitors ; Morphine/pharmacology* ; Nalorphine/pharmacology ; Rats

Acupuncture Therapy ; Analgesia ; Animals ; Brain Chemistry ; Morphine ; pharmacology ; Opium ; analogs & derivatives ; antagonists & inhibitors ; Rats

AIMTo compare the antagonistic effects of 6 beta-naltrexol and naltrexone against morphine analgesia.

METHODSThe effects of 6 beta-naltrexol and naltrexone against morphine analgesia were observed in mouse heat radiant tail-flick assay and in mouse (55 +/- 1) degrees C hot plate test. The displacement of 6 beta-naltrexol and naltrexone on binding to CHO-mu receptor was observed by radioligand binding study.

RESULTS6 beta-naltrexol antagonized morphine analgesia but the potency was (6.1 +/- 1.7)% that of naltrexone. The effective duration of 6 beta-naltrexol was 3-4 times that of naltrexone and the peak time of the response was about 0.5-1 h after s.c. equivalent efficacy dose (ED95) in two models. Like naltrexone, 6 beta-naltrexol was effective by oral administration and the potency ratio of p.o./s.c. was 1/3. As an antagonist to opioid receptor, the displacement of 6 beta-naltrexol was about 12.5% that of naltrexone, which was almost in agreement with the efficacies against morphine analgesia in mouse.

CONCLUSIONCompared with naltrexone, 6 beta-naltrexol was less potent but duration was longer.

Analgesia ; Analgesics, Opioid ; antagonists & inhibitors ; Animals ; Female ; Male ; Mice ; Morphine ; antagonists & inhibitors ; Naltrexone ; analogs & derivatives ; pharmacology ; Narcotic Antagonists ; pharmacology ; Pain Threshold ; drug effects ; Receptors, Opioid, mu ; metabolism

The effects of ginsenosides on the actions of morphine are summarized. It mainly focuses on the antagonistic effects of ginsenosides on morphine-induced changes of animal behaviors, neural system functions and cell signaling transduction.
Animals ; Behavior, Animal ; drug effects ; Body Weight ; drug effects ; Ginsenosides ; pharmacology ; Mice ; Morphine ; antagonists & inhibitors ; pharmacology ; Morphine Dependence ; Neurotransmitter Agents ; metabolism ; Rats ; Signal Transduction ; drug effects

AIMTo determine whether testosterone is involved in morphine withdrawal syndrome (WS).

METHODSIn order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS.

RESULTSThe severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats.

CONCLUSIONIt can be concluded that testosterone might be effectively involved in morphine WS.

Androgen Antagonists ; pharmacology ; Androgens ; pharmacology ; physiology ; Animals ; Behavior, Animal ; Female ; Flutamide ; pharmacology ; Male ; Morphine ; pharmacology ; Morphine Dependence ; physiopathology ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Narcotics ; pharmacology ; Orchiectomy ; Rats ; Rats, Wistar ; Severity of Illness Index ; Substance Withdrawal Syndrome ; physiopathology ; Testosterone ; pharmacology ; physiology

OBJECTIVETo study the acting mechanism of anti-morphine conditioned place preference (CPP) between aqueous extract of Corydalis yanhusuo and L-THP and compare their effects.

METHODThe CPP model was established by injecting morphine in rats with a increasing dose for 10 days, with the initial dose of 10 g x kg(-1) and the final dose of 100 g x kg(-1), 10 mg x kg(-1) was increased each day, thus 100 mg x kg(-1) was injected by d 10. Having been treated with differential doses (2, 1 and 0.5 g x kg(-1)) of C. yanhusuo (containing L-THP: 0.153, 0.077 and 0.038 mg x kg(-1) respectively) and L-THP (3.76, 1.88 and 0.94 mg x kg(-1)) for six days, the CPP effect in rats was detected. Both colorimetry and immunohistochemistry methods were adopted to detect the content of glutamate neurotransmitter in each brain region and the expression of NR2B in VTA-NAc-PFC neuroanatomical circuit.

RESULTCompared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76 and 1.88 mg x kg(-1)) groups showed a notably shorter retention period of rats in white boxes (morphine-accompanied boxes) (P < 0.05 or P < 0.01) and remarkably lower glutamic acid content in VTA, NAc and PFC and NR2B expression.

CONCLUSIONBoth C. yanhusuo and L-THP can substantially inhibit the effect of morphine CPP, reduce the increasing glutamic acid content in VTA-NAc-PFC neuroanatomical circuit and down-regulated NR2B expression, which may be one of mechanisms on reducing the effect of morphine CPP. C. yanhusuo preparations containing L-THP (1 x ) showed 24-fold effect of L-THP monomer of single application in terms of the behaviouristics of inhibitory effect on CPP as well as the similarity in terms of transmitter glutamic acid of in VTA-NAc-PFC neuroanatomical circuit and pharmacological mechanism of NR2B.

Animals ; Berberine Alkaloids ; therapeutic use ; Conditioning, Operant ; drug effects ; Corydalis ; chemistry ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Male ; Morphine ; antagonists & inhibitors ; Morphine Dependence ; drug therapy ; psychology ; Rats ; Rats, Sprague-Dawley

BACKGROUND: Although the efficacy of morphine in a neuropathic pain state is somewhat controversial, intrathecally administered morphine reversed the mechanical allodynia in a previous animal study. Using a behavioral test, we investigated the mechanism of the antiallodynic action of intrathecal morphine by administering opioids, alpha2 adrenergic and cholinergic receptor antagonists in a rat model of neuropathic pain induced by a spinal nerve ligation injury. METHODS: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5th and 6th spinal nerves and insertion of a chronic lumbar intrathecal catheter. Morphine 1 microgram was administered intrathecally to attenuate the mechanical allodynia. Naloxone 10 microgram, yohimbine 30 microgram, prazosin 30 microgram, atropine 10 microgram, pirenzepine 10 microgram, and methoctramine 10 microgram was administered intrathecally before and after the injection of morphine in order to investigate the reversal of an increased allodynic threshold by morphine. The allodynic thresholds for the left hindpaw withdrawal to von Frey hairs were assessed and converted to %MPE. RESULTS: A reduction of mechanical allodynia by intrathecal morphine was produced. Naloxone pretreatment, but not posttreatment, reversed the antiallodynic effect of intrathecal morphine (P < 0.01). All alpha2 adrenergic and cholinergic receptor antagonists used here did not reverse it. CONCLUSIONS: The results suggest that the reversal mechanism of mechanical allodynia by intrathecal morphine appears to be mediated mostly by the opioid receptor system, but not the alpha2 adrenergic and cholinergic receptor systems, at the spinal level in a rat model of a spinal nerve ligation injury.
Analgesics, Opioid ; Animals ; Atropine ; Catheters ; Cholinergic Antagonists ; Hair ; Humans ; Hyperalgesia ; Ligation* ; Male ; Models, Animal ; Morphine* ; Naloxone ; Neuralgia* ; Pirenzepine ; Prazosin ; Rats, Sprague-Dawley ; Receptors, Opioid ; Spinal Nerves* ; Yohimbine

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Humans ; Calcitonin Gene-Related Peptide/antagonists & inhibitors* ; Drug Tolerance ; Hypoglycemic Agents/pharmacology* ; Microglia/physiology* ; MicroRNAs/physiology* ; Minocycline/pharmacology* ; Morphine/pharmacology* ; Neuralgia/etiology* ; Plant Extracts/pharmacology* ; Signal Transduction/physiology*

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

OBJECTIVETo study the effect of glycine site/NMDA (N-methyl-D-aspartate) receptor antagonist MRZ2/576 on the conditioned place preference (CPP) and locomotor activity induced by morphine in mice.

METHODSDifferent doses (1.25, 2.5 and 5 mg/kg, i.p.) of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine (5 mg/kg) in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm.

RESULTSMRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice.

CONCLUSIONBased on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.

Animals ; Conditioning (Psychology) ; drug effects ; Excitatory Amino Acid Antagonists ; pharmacology ; Magnesium ; physiology ; Male ; Mice ; Mice, Inbred ICR ; Morphine ; pharmacology ; Motor Activity ; drug effects ; Phthalazines ; pharmacology ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors