On the Nature of the Intra-Administration Unconditioned Stimulus: Comment on McDonald and Siegel (2004).

R. V. McDonald and S. Siegel (see record 2004-10475-001) present convincing evidence that a small dose of morphine (5 mg/kg) may elicit withdrawal signs in rats previously injected on a number of occasions with a large dose of morphine (50 mg/kg), thus suggesting that intra-administration associations may be involved in drug withdrawal. This finding is important for basic and applied researchers studying drug reward mechanisms. Although R. V. McDonald and S. Siegel point out that the morphine conditional stimulus (CS) and unconditioned stimulus (US) making up the intra-administration association differ in onset and magnitude, the author of this comment argues that the CS and US may also differ in terms of pharmacologic activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gustatory insular cortex lesions disrupt drug-induced, but not lithium chloride-induced, suppression of conditioned stimulus intake.

Rats suppress intake of a normally preferred 0.15% saccharin conditioned stimulus (CS) when it is paired with an aversive agent like lithium chloride (LiCl) or a preferred substance such as sucrose or a drug of abuse. The reward comparison hypothesis suggests that rats avoid intake of a saccharin cue following pairings with a drug of abuse because the rats are anticipating the availability of the rewarding properties of the drug. The present study used bilateral ibotenic acid lesions to examine the role of the gustatory cortex in the suppression of CS intake induced by cocaine, morphine, and LiCl. The results show that bilateral lesions of the insular gustatory cortex (1) fully prevent the suppressive effects of both a 15 and a 30 mg/kg dose of morphine, (2) attenuate the suppressive effect of a 10 mg/kg dose of cocaine, but (3) are overridden by a 20 mg/kg dose of the drug. Finally, these same cortical lesions had no impact on LiCl-induced conditioned taste aversion. The current data show that the insular taste cortex plays an integral role in drug-induced avoidance of a gustatory CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences in analgesic, reinforcing, discriminative, and motoric effects of opioids.

This review summarizes evidence for sex differences in behavioral effects of opioids, primarily in rats. Whereas mu agonists have been found to be more potent and in some cases more efficacious in producing analgesia and sedation in males than females, females are more sensitive than males to reinforcing and locomotor stimulant effects of opioids. Sex differences in motoric effects of opioids may contribute to sex differences in other behavioral effects of opioids; for example, sex differences in rats' ability to discriminate morphine from saline can be attributed entirely to greater morphine-induced sedation in males. Chronic estradiol blunts females' sensitivity to morphine's analgesic and sedative effects, but enhances females' sensitivity to the reinforcing and locomotor stimulant effects of mu opioids. The neurobiological basis for sex differences in and estradiol modulation of behavioral effects of opioids includes brain opioid receptor density (greater in males and under low-estradiol conditions in females) and dopaminergic function (greater in females and under high-estradiol conditions). Given the significant and growing use of opioids by women, both medicinally and recreationally, understanding how female biology influences analgesic and other effects of opioids is crucial. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

LC-MS/MS法测定火锅食品中5种罂粟壳

依据JJF 1059.1—2012《测量不确定度评定与表示》和CNAS—GL06—2019《化学分析中不确定度的评估指南》中不确定度评定的基本程序,通过建立数学模型,建立了高效液相色谱串联质谱法测定火锅食品中吗啡、可待因、罂粟碱、那可丁和蒂巴因含量不确定度的分析方法。结果表明,罂粟碱、那可丁、蒂巴因、吗啡、可待因合成标准不确定度的最终结果分别为5.1×10^-2,5.0×10^-2,5.8×10^-2,8.4×10^-2,8.5×10^-2;影响测量结果不确定度的主要因素是样品回收率,样品平行试验重复性,样品提取,校准曲线拟合,标准工作溶液的配置。从校准曲线拟合这一不确定度分量可以看出,采用内标法进行测定的吗啡和可待因明显优于外标法测量的其他3种物质,可通过内标法进行测定,以降低样品基质不同所引入的不确定度。     

高效液相色谱-串联质谱法快速测定食品中5种罂粟壳生物碱

建立了高效液相色谱-串联质谱法（HPLC-MS/MS）定性定量分析食品中非法添加的吗啡、可待因、蒂巴因、罂粟碱和那可丁等5种罂粟壳生物碱。采用Capcell PAK C18 TYPE MGⅡ（5 μm×2.0 mm×150 mm）色谱柱分离,以10 mmol/L乙酸铵（pH 4.2）-乙腈为流动相,梯度洗脱,电喷雾离子源,多反应监测（MRM）模式检测。在优化的实验条件下,得到了较宽的线性范围和较低的定量检出限。吗啡和可待因的线性范围为1.0~20.0 μg/L,蒂巴因、罂粟碱和那可丁的线性范围为0.2~4.0 μg/L,相关系数均在0.999以上。食品中吗啡、可待因、蒂巴因、罂粟碱和那可丁的定量限分别为7.5、7.5、1.5、1.5、 1.5 μg/kg。方法的回收率和重现性较好,5种罂粟壳生物碱的回收率在72.2%~111.4%之间,相对标准偏差（RSD）在3.1%~8.8%之间。该方法操作简单、灵敏度高、准确可靠,可用于食品中5种非法添加罂粟壳生物碱的定量及确证分析。     

Magnesium and Morphine in the Treatment of Chronic Neuropathic Pain–A Biomedical Mechanism of Action

The effectiveness of opioids in the treatment of neuropathic pain is limited. It was demonstrated that magnesium ions (Mg²⁺), physiological antagonists of N-methyl-D-aspartate receptor (NMDAR), increase opioid analgesia in chronic pain. Our study aimed to determine the molecular mechanism of this action. Early data indicate the cross-regulation of µ opioid receptor (MOR) and NMDAR in pain control. Morphine acting on MOR stimulates protein kinase C (PKC), while induction of NMDAR recruits protein kinase A (PKA), leading to a disruption of the MOR-NMDAR complex and promoting functional changes in receptors. The mechanical Randall-Selitto test was used to assess the effect of chronic Mg²⁺ and morphine cotreatment on streptozotocin-induced hyperalgesia in Wistar rats. The level of phosphorylated NMDAR NR1 subunit (pNR1) and phosphorylated MOR (pMOR) in the periaqueductal gray matter was determined with the Western blot method. The activity of PKA and PKC was examined by standard enzyme immunoassays. The experiments showed a reduction in hyperalgesia after coadministration of morphine (5 mg/kg intraperitoneally) and Mg²⁺ (40 mg/kg intraperitoneally). Mg²⁺ administered alone significantly decreased the level of pNR1, pMOR, and activity of both tested kinases. The results suggest that blocking NMDAR signaling by Mg²⁺ restores the MOR-NMDAR complex and thus enables morphine analgesia in neuropathic rats.     

Dopamine D4 Receptor Counteracts Morphine-Induced Changes in μ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [³⁵S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D₄ receptor (D₄R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [³H]DAMGO B_max values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to G_i/0 protein, the present results give support for the existence of antagonistic functional D₄R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine.     

火锅底料中吗啡组分的检测方法研究

采用高效液相色谱法,将组分从固体中转移到液体中是保障定量结果符合真实值的前提,将甲醇溶解法确定为前处理的基本方法。火锅底料中吗啡含量为5．51％、7．60％、10．20％,以C18柱为分析柱,使用国产固相萃取小柱可以得到98．7％的回收率。流动相0．05mol／L磷酸二氢钾、0．0025mol／L庚烷磺酸钠水溶液．乙腈;柱温35℃;流速1mL／min;检测波长220mm,分析了火锅底料中的吗啡。     

吸毒者尿样中3-β-D-葡萄糖醛酸吗啡、吗啡、O~6-单乙酰吗啡和可待因的LC-MS/MS分析

建立吸毒者尿样中3-β-D-葡萄糖醛酸吗啡、吗啡、O6-单乙酰吗啡、可待因的液相色谱-串联质谱分析方法。尿样经固相萃取后,用C18液相柱分离,以含甲酸铵和甲酸的水、乙腈为流动相等度洗脱,采用电喷雾电离(ESI+),多反应监测(MRM)模式检测目标化合物。以化合物的保留时间、2对母离子/子离子对定性,尿样中3-β-D-葡萄糖醛酸吗啡的检测限为0.5μg.L-1,吗啡、O6-单乙酰吗啡、可待因的检测限为0.1μg.L-1;线性关系良好,相关系数r在0.998以上;日内及日间精密度均在10%以内。该方法快速、灵敏、简便、可靠,能同时分析吸毒者尿样中的3-β-D-葡萄糖醛酸吗啡、吗啡、O6-单乙酰吗啡和可待因。     

Tegmental pedunculopontine glutamate and GABA-B synapses mediate morphine reward.

The tegmental pedunculopontine nucleus (TPP) of the midbrain is critical in mediating the acute rewarding effects of opiates. However, the circuitry and neurochemistry underlying this effect has not been determined. Here we identify TPP receptors and cell types involved in systemic morphine reward and suggest an anatomical and neurochemical model for reward in the TPP. Simple hypothetical anatomical models for serial cell arrangements and receptors in the TPP were proposed and predictions of behavioral outcome (reward or no reward) then were made, based on the administration of agonists and antagonists directly into the TPP of rats. We report that TPP-administered NMDA produced rewarding effects, although GABA agonists and antagonists had no motivational effects on their own. However, the NMDA receptor antagonist AP-7 and the GABA-B receptor antagonist saclofen, while having no motivational effects on their own, blocked systemic morphine reward as measured by conditioned place preference. These results provide positive evidence for GABA-B and glutamate synapses in the TPP, which mediates systemic morphine reward and suggest that a serial pathway for morphine reward in the TPP is unlikely. (PsycINFO Database Record (c) 2010 APA, all rights reserved)