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Maria Pannell, Dominika Labuz, Melih Ö Celik, Jacqueline Keye, Arvind Batra, Britta Siegmund, Halina Machelska
BACKGROUND: During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. METHODS: Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4...
October 7, 2016: Journal of Neuroinflammation
William A Carlezon, Andrew D Krystal
Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry...
October 2016: Depression and Anxiety
Ashlee Van't Veer, Karen L Smith, Bruce M Cohen, William A Carlezon, Anita J Bechtholt
INTRODUCTION: Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front-line treatment for alcoholism in humans. Although roles for mu- and delta-opioid receptors have been characterized, the contribution of kappa-opioid receptors (KORs) is less clear. There is evidence that changes in KOR system function can decrease or increase EtOH drinking, depending on test conditions...
September 2016: Brain and Behavior
Sara M Hall, Lindsay LeBaron, Cyf Ramos-Colon, Chaoling Qu, Jennifer Yanhua Xie, Frank Porreca, Josephine Lai, Yeon Sun Lee, Victor J Hruby
Dynorphin A (Dyn A) is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors with a preference for the kappa receptor but also neuroexcitatory effects, which cause hyperalgesia. We have shown that the neuroexcitatory effects are mediated through bradykinin (BK) receptors and that intrathecal ( administration of our lead ligand 1, [des-Arg(7)]-Dyn A-(4-11), which shows good binding affinity (IC50 = 150 nM) at the BK receptors, blocks Dyn A-induced hyperalgesia in naïve animals and reverses thermal and tactile hypersensitivities in a dose-dependent manner in nerve-injured animals...
September 27, 2016: ACS Chemical Neuroscience
Dominika Labuz, Melih Ö Celik, Andreas Zimmer, Halina Machelska
Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively...
2016: Scientific Reports
Qian Huang, Xiao-Fang Mao, Hai-Yun Wu, Teng-Fei Li, Ming-Li Sun, Hao Liu, Yong-Xiang Wang
BACKGROUND: Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao) has been prescribed to manage chronic pain, arthritis, and traumatic injuries. Bullatine A, a C20-diterpenoid alkaloid, is one of its principle effective compounds. This study aimed to investigate the anti-hypersensitivity of bullatine A in a variety of rat pain models and explore its mechanisms of action. METHODS: Rat neuropathic pain, inflammatory pain, diabetic neuropathic pain, and bone cancer pain models were used...
2016: Journal of Neuroinflammation
Juan Li, Xiaojie Liang, Yaguang Zhou, Shumiao Zhang, Fan Yang, Haitao Guo, Rong Fan, Na Feng, Min Jia, Yueming Wang, Mingchao Liu, Jianming Pei
Previously study showed κ-opioid receptor stimulation with exogenous κ-opioid receptor agonist elicited a protective effect against hypoxic pulmonary hypertension (HPH). However, the effect of endogenous κ-opioid receptor agonist dynorphin A on HPH remains unclear. This study was to determine the role of dynorphin in HPH. Hypoxia for 2 weeks induced HPH. Compared with the HPH group, the HPH + nor-BNI (a selective κ-opioid receptor antagonist) group showed a significant increase in mean pulmonary arterial pressure (mPAP)...
August 25, 2016: European Journal of Pharmacology
Roger Negrete, María Salud García Gutiérrez, Jorge Manzanares, Rafael Maldonado
Joint pain is a major clinical problem mainly associated to osteoarthritis, and characterized by articular cartilage degradation resulting in a complex chronic pain state that includes nociceptive, emotional and cognitive manifestations. Memory impairment, depressive- and anxiety-like symptoms have been reported to be associated with chronic pain, leading to a decrease of life quality. In this study, we evaluated the involvement of the endogenous dynorphin/kappa opioid receptor (KOR) system on the nociceptive, emotional, cognitive, neurochemical and epigenetic manifestations of joint pain...
August 24, 2016: Neuropharmacology
Jian Qiu, Casey C Nestor, Chunguang Zhang, Stephanie L Padilla, Richard D Palmiter, Martin J Kelly, Oline K Rønnekleiv
Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1(ARH)) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1(ARH) neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice...
2016: ELife
Maria Cernea, Rebecca Phillips, Vasantha Padmanabhan, Lique M Coolen, Michael N Lehman
Insulin serves as a link between the metabolic and reproductive systems, communicating energy availability to the hypothalamus and enabling reproductive mechanisms. Adult Suffolk ewes prenatally exposed to testosterone (T) display an array of reproductive and metabolic dysfunctions similar to those seen in women with polycystic ovarian syndrome (PCOS), including insulin resistance. Moreover, prenatal T treatment alters neuropeptide expression in KNDy (co-expressing kisspeptin, neurokinin B/dynorphin) and agouti-related peptide (AgRP) neurons in the arcuate nucleus, two populations that play key roles in the control of reproduction and metabolism, respectively...
October 2016: European Journal of Neuroscience
Haiqing Liu, Yanjun Tian, Bingyun Ji, Hai Lu, Qing Xin, Yunlu Jiang, Liangcai Ding, Jingmei Zhang, Jing Chen, Bo Bai
Together with its endogenous ligands (dynorphin), the kappa opioid receptor (KOR) plays an important role in modulating various physiological and pharmacological responses, with a classical G protein-coupled pathway mediating analgesia and non-G protein-dependent pathway, especially the β-arrestin-dependent pathway, eliciting side effects of dysphoria, aversion, drug-seeking in addicts, or even relapse to addiction. Although mounting evidence has verified a functional overlap between dynorphin/KOR and neurotensin/neurotensin receptor 1 (NTSR1) systems, little is known about direct interaction between the two receptors...
August 12, 2016: Biochimica et Biophysica Acta
Jennifer A Yang, Ali Yasrebi, Marisa Snyder, Troy A Roepke
Arcuate neurons that coexpress kisspeptin (Kiss1), neurokinin B (Tac2), and dynorphin (Pdyn) mediate negative feedback of 17β-estradiol (E2) on the HPG axis. Previous studies report that fasting and caloric restriction reduce arcuate Kiss1 expression. The objective of this study was to determine the interactions of E2 with fasting, caloric restriction, and diet-induced obesity on KNDy gene and receptor expression. Ovariectomized female mice were separated into control and estradiol benzoate (E2B)-treated groups...
December 5, 2016: Molecular and Cellular Endocrinology
George F Koob, Nora D Volkow
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala...
August 2016: Lancet Psychiatry
Jamie H Rose, Anushree N Karkhanis, Björn Steiniger-Brach, Sara R Jones
The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood...
2016: International Journal of Molecular Sciences
Puneet Kaur Randhawa, Amteshwar Singh Jaggi
Remote ischemic preconditioning (RIPC) is an intriguing process whereby transient regional ischemia and reperfusion episodes to remote tissues including skeletal, renal, mesenteric provide protection to the heart against sustained ischemia-reperfusion-induced injury. Clinically, this technique has been used in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention, and heart valve surgery. The endogenous opioid system is extensively expressed in the brain to modulate pain sensation...
July 26, 2016: Journal of Cardiovascular Pharmacology and Therapeutics
Anushree N Karkhanis, Kimberly N Huggins, Jamie H Rose, Sara R Jones
Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade...
November 2016: Neuropharmacology
Sarantis Livadas, George P Chrousos
PURPOSE OF REVIEW: The mechanism of puberty initiation remains an enigma, despite extensive research in the field. Pulsatile pituitary gonadotropin secretion under the guidance of hypothalamic gonadotropin-releasing hormone (GnRH) constitutes a sine qua non for pubertal onset. In turn, the secretion of GnRH in the human hypothalamus is regulated by kisspeptin and its receptor as well as by permissive or opposing signals mediated by neurokinin B and dynorphin acting on their respective receptors...
August 2016: Current Opinion in Pediatrics
Ayumu Inutsuka, Akira Yamashita, Srikanta Chowdhury, Junichi Nakai, Masamichi Ohkura, Toru Taguchi, Akihiro Yamanaka
The level of wakefulness is one of the major factors affecting nociception and pain. Stress-induced analgesia supports an animal's survival via prompt defensive responses against predators or competitors. Previous studies have shown the pharmacological effects of orexin peptides on analgesia. However, orexin neurons contain not only orexin but also other co-transmitters such as dynorphin, neurotensin and glutamate. Thus, the physiological importance of orexin neuronal activity in nociception is unknown. Here we show that adult-stage selective ablation of orexin neurons enhances pain-related behaviors, while pharmacogenetic activation of orexin neurons induces analgesia...
2016: Scientific Reports
Shakunthala Narayanaswamy, Julia K Prague, Channa N Jayasena, Deborah A Papadopoulou, Maria Mizamtsidi, Amar J Shah, Paul Bassett, Alexander N Comninos, Ali Abbara, Stephen R Bloom, Johannes D Veldhuis, Waljit S Dhillo
CONTEXT: A subpopulation of hypothalamic neurons colocalize three neuropeptides, namely kisspeptin, neurokinin B (NKB), and dynorphin, collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates, and dynorphin (an opioid) inhibits. OBJECTIVE: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of the coadministration of kisspeptin-54, NKB, and an opioid receptor antagonist, naltrexone, on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release...
September 2016: Journal of Clinical Endocrinology and Metabolism
S Ly Wu, A Wn Leung, D Tw Yew
Opioid is a popular drug of abuse and addiction. We evaluated acupuncture as a non-pharmacological treatment with a focus on managing withdrawal symptoms. Electrical stimulation at a low frequency (2 Hz) accelerates endorphin and encephalin production. High-frequency stimulation (100 Hz) up-regulates the dynorphin level that in turn suppresses withdrawal at the spinal level. The effect of 100-Hz electroacupuncture may be associated with brain-derived neurotrophic factor activation at the ventral tegmental area, down-regulation of cAMP response element-binding protein, and enhanced dynorphin synthesis in the spinal cord, periaqueductal grey, and hypothalamus...
June 2016: East Asian Archives of Psychiatry: Official Journal of the Hong Kong College of Psychiatrists
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