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Exposure to organophosphate insecticides induces undesirable behavioral changes in humans, including anxiety and irritability, depression, cognitive disturbances and sleep disorders. Little information currently exists concerning the neural mechanisms underlying such behavioral changes. The brain stem locus coeruleus (LC) could be a mediator of organophosphate insecticide-induced behavioral toxicities since it contains high levels of acetylcholinesterase and is involved in the regulation of the sleep-wake cycle, attention, arousal, memory, and pathological processes, including anxiety and depression. In the present study, using a multi-wire recording technique, we examined the effects of methyl parathion, a commonly used organophosphate insecticide, on the firing patterns of LC neurons in rats. Systemic administration of a single dose of methyl parathion (1 mg/kg, i.v.) increased the spontaneous firing rates of LC neurons by 240% but did not change the temporal relationships among the activities of multiple LC neurons. This dose of methyl parathion induced a 50% decrease in blood acetylcholinesterase activity and a 48% decrease in LC acetylcholinesterase activity. The methyl parathion-induced excitation of LC neurons was reversed by administration of atropine sulfate, a muscarinic receptor antagonist, indicating an involvement of muscarinic receptors. The methyl parathion-induced increase in LC neuronal activity returned to normal within 30 min while the blood acetylcholinesterase activity remained inhibited for over 1 h. These data indicate that methyl parathion treatment can elicit excitation of LC neurons. Such excitation could contribute to the neuronal basis of organophosphate insecticide-induced behavioral changes in human.

Background: Lysosomal acid lipase (LAL), a lysosomal enzyme is able to degrade cholesteryl esters to free fatty acids and cholesterol. The information on the association of LAL with malignancies is limited. This study is to determine the difference in expression level of LAL between benign and malignant tissues among human organs. Method: Immunohistochemistry (IHC) for human LAL was performed on A tissue microarray (TMA) containing 360 benign and malignant tissues from 36 human organs. The expression level of LAL was represented by an IHC score calculated by multiplying area score (0-3) with intensity score (0-3), ranged from 0 to 9. Student’s t-test was used to compare the mean IHC score between benign and malignant tissues in same organs. Results: Eighteen out of 36 human organs have IHC stains on both benign and malignant tissues. As shown in Table 1, LAL expression level was higher in malignancy than in benign tissues in 9 organs. The difference in LAL expression level was significantly (or nearly lower in malignant tissues of adrenal gland, stomach, liver, testis and kidney. Conclusion: The expression level of LAL varies among human organs. As compared with elevation of LAL expression level, decreased expression level of LAL in malignancies could be of more significance. Table 1Difference in expression level of LALOrganmalignantBenignpM/BnMeanSEnMeanSEvalueRatioAdrenal Gland31.670.73560.950.02-1.36Stomach131.170.4583.130.820.035-2.7Liver131.350.3483.560.490.001-2.6Larynx80.250.0940.630.380.22-2.5Testis41.630.4743.750.750.054-2.3Uterus131.620.4272.570.970.302-1.6Kidney122.920.3134.50.870.051-1.5Prostate152.970.51441.22.389-1.3Urinary Bladder110.680.1750.70.30.9561Cervix41.630.4751.250.560.6361.3Colon162.340.3991.50.280.1451.6Esophagus41.630.992100.6951.6Ovary43.631.0741.940.930.2781.9Skin83.591.3251.850.720.3491.9Breast142.860.5861.380.550.1392.1Pancreas101.80.5590.830.140.1262.2Brain32.170.4450.80.560.144`2.7Lung81.970.7450.600.290.193.3 Citation Format: Mohamed EI Gassim, Jinghe Mao, Tangen Ma, Xinchun Zhou. Differential expression of lysosomal acid lipase (LAL) between benign and malignant tissues among human organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5421. doi:10.1158/1538-7445.AM2017-5421

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, kappa-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10:1) significantly attenuated the development of dependence on morphine. The elevation of [3H]MK-801 binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.