Ameliorative Potential of Morin in Streptozotocin-Induced Neuropathic Pain in Rats

Purpose: To investigate the protective effect of morin, a naturally occurring bioflavonoid of Moraceae family, in experimentally-induced diabetic neuropathy (DN) in rats.Methods: Diabetes was induced by a single injection (65 mg/kg, ip) of streptozotocin (STZ). Morin (15 and 30 mg/kg/day) oral treatment was started 3 weeks after diabetes induction and continued for 5 consecutive weeks. Pain threshold behavior tests were performed at the end of the treatment. In sciatic nerve, inflammatory cytokines (TNF-á, IL-1â, IL-6), nerve growth factor (NGF) and insulin growth factor (IGF-1) were determined using ELISA kits, while thiobarbituric acid reactive substances (TBARS),glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were assessed.Results: Diabetic animals showed apparent decreased paw-withdrawal (39 %, p < 0.05) and tail-flick (31 %, p < 0.05) latency as compared with control group. All the measured biomarkers were altered (p < 0.05 to 0.001) in diabetic rats compared with control non-diabetic animals. Morin treatment attenuated hyperalgesia and analgesia (p < 0.05) respectively. Morin treatment of diabetic rats at both doses significantly decreased the levels of cytokines (p < 0.01), glucose (p < 0.01) and TBARS (p < 0.001), but increased NGF (p < 0.01), IGF-1 (p < 0.01) and GSH (p < 0.01) levels in sciatic nerves compared to untreated diabetic animals. Inhibited activities (U/mg protein) of SOD (1.08 ± 0.16) and CAT (2.77 ± 0.36) in sciatic nerve of diabetic rats also found corrections (2.09 ± 0.11, p < 0.01) and (4.53 ± 0.57, p < 0.01) after morin (30 mg/kg/day) treatment, compared with untreated diabetic animals.Conclusion: These findings demonstrate the protective effect of morin mediated through reduction of oxidative stress and inflammatory process, and suggest the therapeutic potential of morin in the attenuation of diabetic neuropathy.Keywords: Morin, Diabetes, Neuropathy pain, Oxidative stress, Anti-inflammator

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability

Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol smokers requires identifying the neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) neurons in the ventral tegmental area (VTA) mediate the positive reinforcing effects of nicotine. Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates

The nicotine + alcohol interoceptive drug state: contribution of the components and effects of varenicline in rats

RATIONALE: Nicotine and alcohol co-use is highly prevalent, and as such, individuals experience the interoceptive effects of both substances together. Therefore, examining sensitivity to a compound nicotine and alcohol (N+A) interoceptive cue is critical to broaden our understanding of mechanisms that may contribute to nicotine and alcohol co-use. OBJECTIVES: This work assessed the ability of a N+A interoceptive cue to gain control over goaltracking behavior and determined the effects of the α4β2 nicotinic partial agonist and smoking cessation compound varenicline on sensitivity to N+A. METHODS: Two groups of male Long-Evans rats were trained to discriminate N+A (0.4 mg/kg nicotine + 1 g/kg alcohol, IG) from water under two different training conditions using a Pavlovian drug discrimination task. The effects of varenicline (0, 1, 3 mg/kg, IP) administered alone and on sensitivity to N+A and the components were determined. RESULTS: Under both training conditions, N+A rapidly gained control over behavior, with a greater contribution of nicotine to the N+A compound cue. Varenicline fully substituted for the N+A training dose and varenicline (1 mg/kg) enhanced sensitivity to the lowest N+A dose (0.1N+0.1A). Given the high selectivity of varenicline for the α4β2 receptor, this finding suggests a functional role for α4β2 nicotinic acetylcholine receptors (nAChR) in modulating sensitivity to N+A. CONCLUSIONS: The N+A compound cue is a unique cue that is modulated in part, by activity at the α4β2 nAChR. These findings advance understanding of the interoceptive effects of nicotine and alcohol in combination and may have implications in relation to their co-use