Inhibitory and disinhibitory effects of psychomotor stimulants and depressants on the sexual behavior of male and female rats

Drugs of abuse comprise several pharmacological classes, including psychomotor stimulants, such as amphetamine and cocaine, and CNS depressants, such as morphine and alcohol. Few studies have examined the effects of those drugs systematically on human sexual behavior, although substantial clinical and epidemiological literatures suggest that drugs in both classes either inhibit sexual responding or can be “prosexual” in certain situations, thereby increasing the potential of risky sexual activity and the spread of sexually transmitted diseases. This paper reviews original data in rats showing that both classes of drug inhibit or disinhibit sexual behavior depending on the animal's baseline level of sexual responding, hormonal status, whether the drug is given acutely or chronically, and whether the animal has learned to inhibit sexual responding toward nonreceptive partners or in the presence of conditioned olfactory cues that predict sexual nonreward.     

Assessment of oxidative damage induced by acute doses of morphine sulfate in postnatal and adult rat brain

The aim of the present study is to evaluate the oxidative damage in rats of different ages. Weaned rats of 25 g and adults of 300 g were used in groups of 6, a single i.p. dose of morphine sulfate of 3, 6 or 12 mg/kg was administered. All animals were sacrificed to measure GSH and 5-HT levels in brain by liquid chromatography, as well as Na⁺, K⁺-ATPase and total ATPase enzymatic activity. 5-HT levels decreased significantly (p<0.05) in adult animals that received 3 and 6 mg morphine. Na⁺, K⁺-ATPase activity increased significantly (p<0.05) in all groups of weaned animals. In adult animals, Na⁺, K⁺-ATPase and total ATPase partially diminished. GSH levels diminished significantly (p<0.05) both in weaned and in adult groups. The results indicate age-induced changes in cellular regulation and biochemical responses to oxidative stress induced by morphine.     

The possible involvement of endogenous ligands for mu-, delta- and kappa-opioid receptors in modulating morphine-induced CPP expression in rats

Previous studies suggested that electroacupuncture (EA) can suppress opioid dependence by the release of endogenous opioid peptides. To explore the site of action and the receptors involved, we tried to inject highly specific agonists for μ-, δ- and κ-opioid receptors into the CNS to test whether it can suppress morphine-induced conditioned place preference (CPP) in the rat. Male Sprague–Dawley rats were trained with 4 mg/kg morphine, i.p. for 4 days to establish the CPP model. This CPP can be prevented by (a) i.p. injection of 3 mg/kg dose of morphine, (b) intracerebroventricular (i.c.v.) injection of micrograms doses of the selective μ-opioid receptor agonist DAMGO, δ-agonist DPDPE or κ-agonist U-50,488H or (c) microinjection of DAMGO, DPDPE or U50488H into the shell of the nucleus accumbens (NAc). The results suggest that the release of endogenous μ-, δ- and κ-opioid agonists in the NAc shell may play a role for EA suppression of opiate addiction.     

Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention

It has been known that the reinforcing effects and long-term consequences of morphine are closely associated with nucleus accumbens (NAc) in the brain, a key region of the mesolimbic dopamine pathway. However, the proteins involved in neuroadaptive processes and withdrawal symptom in primates of morphine dependence have not been well explored. In the present study, we performed proteomes in the NAc of rhesus monkeys of morphine dependence and withdrawal intervention with clonidine or methadone. Two-dimensional electrophoresis was used to compare changes in cytosolic protein abundance in the NAc. We found a total of 46 proteins differentially expressed, which were further identified by mass spectrometry analysis. The identified proteins can be classified into 6 classes: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. Importantly, we discovered 14 proteins were significantly but similarly altered after withdrawal therapy with clonidine or methadone, revealing potential pharmacological strategies or targets for the treatment of morphine addiction. Our study provides a comprehensive understanding of the neuropathophysiology associated with morphine addiction and withdrawal therapy in primate, which is helpful for the development of opiate withdrawal pharmacotherapies.     

Morphine-element interactions – The influence of selected chemical elements on neural pathways associated with addiction

Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.     

Immunoaffinity extraction of morphine, morphine-3-glucuronide and morphine-6-glucuronide from blood of heroin victims for simultaneous high-performance liquid chromatographic determination

The development of an immunoaffinity-based extraction method for the determination of morphine and its glucuronides in human blood is described. For the preparation of an immunoadsorber, specific antisera (polyclonal, host: rabbit) against morphine, morphine-3-glucuronide and morphine-6-glucuronide were coupled to 1,1′-carbonyldiimidazole-activated trisacrylgel and used for immunoaffinity extraction of morphine and its glucuronides from coronary blood. The resulting extracts were analysed by HPLC with native fluorescence detection. The mean recoveries from spiked blood samples were 71%, 76% and 88% for morphine, morphine-3-glucuronide and morphine-6-glucuronide, respectively. The limit of detection was 3 ng/g blood and the limit of quantitation was 10 ng/g blood for all three analytes. The results of the analysis of coronary blood samples from 23 fatalities due to heroin are presented.     

新克痛宁术后镇痛效果观察

目的了解眼镜蛇毒制剂新克痛宁对术后镇痛效果。方法对７２例胫腓骨折病人,在连续硬膜外阻滞麻醉下行切开复位内固定术,术后随机分为４组（每组１８例）向硬膜外腔注药：Ａ组新克痛宁０．２５ＩＵ／ｋｇ;Ｂ组新克痛宁０．１２５ＩＵ／ｋｇ加０．５％利多卡因液１０ｍｌ;Ｃ组吗啡２ｍｇ;Ｄ组吗啡１ｍｇ加０．５％利多卡因液１０ｍｌ。结果镇痛持续时间Ａ、Ｂ组明显延长,Ａ与Ｂ组分别为（４１２±２８）ｍｉｎ,与Ｃ、Ｄ组比较差异显著（Ｐ＜０．０５）。注药后３０～１２０ｍｉｎ,患肢足背皮肤温度,Ａ、Ｂ组亦高于Ｃ、Ｄ组（Ｐ＜０．０５）,且无不良反应。结论新克痛宁术后镇痛效果比吗啡好。     

Pharmacological Characterization of Morphine-Induced In Vivo Release of Cholecystokinin in Rat Dorsal Horn

Previous studies indicate that an increased release of cholecystokinin (CCK) in response to morphine administration may counteract opioid-induced analgesia at the spinal level. In the present study we used in vivo microdialysis to demonstrate that systemic administration of antinociceptive doses of morphine (1-5 mg/kg, s.c.) induces a dose-dependent and naloxone-reversible release of CCK-like immunoreactivity (CCK-LI) in the dorsal horn of the spinal cord. A similar response could also be observed following perfusion of the dialysis probe for 60 min with 100 microM but not with 1 microM morphine. The CCK-LI release induced by morphine (5 mg/kg, s.c.) was found to be calcium-dependent and tetrodotoxin-sensitive (1 microM in the perfusion medium). Topical application of either the L-type calcium channel blocker verapamil (50 microg) or the N-type calcium channel blocker omega-conotoxin GVIA (0.4 microg) onto the dorsal spinal cord completely prevented the CCK-LI release induced by morphine (5 mg/kg, s.c.). Our data indicate that activation of L- and N-type calcium channels is of importance for morphine-induced CCK release, even though the precise site of action of morphine in the dorsal horn remains unclear. The present findings also suggest a mechanism for the potentiation of opioid analgesia by L- and N-type calcium channel blocking agents.     

Carrier-mediated processes at several rat brain interfaces determine the neuropharmacokinetics of morphine and morphine-6-beta-D-glucuronide

We investigated whether capacity-limited transport processes were involved in morphine and morphine-6-beta-D-glucuronide (M6G) neuropharmacokinetics, at the level of the blood-brain barrier (BBB), the brain extra- and intra-cellular fluids (bECF/bICF), and the bECF/cerebrospinal fluid (CSF) interfaces. We performed transcortical retrodialysis in the rat, by perfusing morphine or M6G through the microdialysis probe in the presence or absence of probenecid. We measured for each compound the in vitro and in vivo (R(D)) probe recoveries. The in vivo R(D), which takes into account the permeability of the tissue surrounding the probe, informs about the morphine and M6G distribution capabilities from bECF to adjacent fluids (bICF, CSF, plasma). We also measured plasma and CSF concentrations at three time points after having added probenecid or not. Finally, we tested several pharmacokinetic models, assuming first-order or capacity-limited processes at each brain interface, to describe experimental morphine and M6G concentrations previously obtained in rat plasma and brain fluids. We found that morphine distributes more easily outside bECF than M6G. Adding probenecid caused a 2-fold decrease and a 1.3-fold increase in morphine and M6G R(D), respectively, and 30 min after adding probenecid, plasma and CSF concentrations increased for M6G but not for morphine. The pharmacokinetic model that gave the best fit included capacity-limited processes at the BBB and bECF/bICF interface for morphine and at the BBB and bECF/CSF interface for M6G. In conclusion, morphine accumulates into brain cells thanks to a probenecid-sensitive transporter located at the bECF/bICF interface, whereas M6G is trapped in bECF thanks to transporters located at the BBB and the bECF/CSF interface.