neuropeptide-y and Morphine-Dependence

Opioid addiction is a brain disease that severely harms society and personal health. Although the tremendous numbers of patients worldwide and emerged negative events, effective treatments for opioid addiction are still lacking. Neuropeptide Y (NPY) is one of the main orexigenic peptides that play vital roles in food intake and energy metabolism. However, increasing evidence indicates that NPY may have great potential in mediating reward effects and drug dependence. In the present study, we assessed the expression changes of NPY in the nucleus accumbens at different timepoints following morphine conditioned place preference (CPP) and investigated the functional importance of potential NPY changes. Our results showed that NPY expression significantly decreased in the nucleus accumbens shell (AcbSh) immediately after chronic morphine exposure. Subsequently, it increased rapidly at first and then gradually returned to normal levels. Further data indicated that these NPY changes were involved in morphine reward memory, demonstrated by a reduction in the extinction period after blocking of the Y5 receptor by L-152,804 in the AcbSh and a prolonged duration of the extinction period following the application of NPY. More importantly, the additional results revealed that L-152,804 also remarkably suppressed the reinstatement of morphine CPP. Together, our results indicate that a complicated plasticity of the NPY pathway in AcbSh occurs following morphine CPP, and this plasticity plays an important role in modulating morphine reward memory. These findings may enhance our understanding of the role of the NPY system in opioid addiction and indicate a promising target for opioid addiction treatment.

Topics: Animals; Conditioning, Classical; Conditioning, Operant; Conditioning, Psychological; Extinction, Psychological; Male; Morphine; Morphine Dependence; Narcotics; Neuronal Plasticity; Neuropeptide Y; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reward

Morphine suppresses a number of immune parameters, such as natural killer (NK) cell activity and lymphocyte proliferation, by acting through mu-opioid receptors in the central nervous system. Prior studies have implicated the sympathetic nervous system in mediating the immunomodulatory effects of acute morphine treatment. However, the peripheral mechanism whereby morphine inhibits NK cell activity is not fully understood. The aim of the present study was to investigate the role of the sympathetic transmitter neuropeptide Y (NPY) in mediating morphine-induced immune alterations. The results showed that administration of the selective NPY Y1 receptor antagonist BIBP3226 blocked morphine's effect on splenic NK activity but did not attenuate the suppression splenocyte proliferative responses to Con-A or LPS. Furthermore, intravenous NPY administration produced a dose-dependent inhibition of splenic NK activity but did not suppress lymphocyte proliferation. Recent studies from our laboratory have demonstrated that morphine modulates NK activity through a central mechanism that requires the activation of dopamine D1 receptors in the nucleus accumbens. Results from the present study showed that microinjection of the D1 receptor agonist SKF-38393 into the nucleus accumbens shell induced a suppression of NK activity that was reversed by BIBP3226. Collectively, these findings demonstrate that NPY Y1 receptors mediate morphine's suppressive effect on NK activity and further suggest that opioid-induced increases in nucleus accumbens D1 receptor activation inhibit splenic NK activity via NPY released from the sympathetic nervous system.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Anti-Anxiety Agents; Arginine; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Down-Regulation; Drug Interactions; Immune Tolerance; Killer Cells, Natural; Male; Morphine; Morphine Dependence; Narcotics; Neuroimmunomodulation; Neuropeptide Y; Nucleus Accumbens; Rats; Rats, Inbred Lew; Receptors, Dopamine D1; Receptors, Neuropeptide Y; Spleen; Sympathetic Nervous System

Neuropeptide Y (NPY) was previously shown in our laboratory to attenuate behavioral signs of morphine withdrawal. To further characterize the anti-withdrawal effect of NPY, the present study attempted to identify specific brain regions where NPY inhibits neuronal activity during withdrawal. Morphine dependence was induced in male Wistar rats by two daily subcutaneous injections of morphine at increasing doses, and the withdrawal syndrome was precipitated acutely by intraperitoneal administration of naloxone. Rats were pre-treated with an intracerebroventricular (icv) injection of NPY (12 nmol) or vehicle 30 min before the naloxone challenge. Withdrawal behavior was quantified using a point scoring technique based on motor- and non-motor-related signs. Brain areas involved in the attenuation of morphine withdrawal were delineated by radioactive in situ hybridization for the immediate early gene c-fos, which is a marker for neuronal activity. The present study confirmed the inhibitory effect of NPY on withdrawal behavior. Inhibition of behavioral signs of naloxone-precipitated morphine withdrawal was accompanied by significantly reduced c-fos expression in the locus coeruleus, lateral septal nucleus, ventral part of the periaqueductal grey, cingulate and frontal cortices, and septohippocampal nucleus. Our data suggest that neo- and allo-cortical areas as well as specific brainstem nuclei are involved in the anti-withdrawal effects of NPY.

Topics: Animals; Brain; Genes, fos; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Neuropeptide Y; Rats; Rats, Wistar; RNA, Messenger; Substance Withdrawal Syndrome