The topicality of kappa-opioid receptor antagonism in pharmacodynamic profile of opioid receptors antagonists

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Health & Medicine

Published on June 9, 2014

Author: FaridShagiakhmetov


Актуальность κ-опиоидных рецепторов в механизме действия опиоидных антагонистов Шагиахметов Фарид

Современная концепция формирования аддиктивных расстройств

Центральное звено «системы вознаграждения» Ventral tegmental area GABA + Enk Mesolimbic pathway Ventral tegmental area Nucleus accumbens Dopamine Ventral striatum Mesencephalon REWARD

Brain reward circuitry Нейрональные контуры «системы вознаграждения» A highly simplified hypothetical scheme by which kappa-opioid receptors in the mesocorticolimbic system might regulate reward and mood. Dopamine neurons originating in the ventral tegmental area (VTA) project to the nucleus accumbens (NAc). Within the NAc, DA acts upon two populations of medium spiny (GABAergic) neurons. One type of neuron expresses dopamine D2 receptors and enkephalin (Enk). DA binding at D2 receptors activates inhibitory G-proteins (Gi) and decreases the activity of these neurons, which enables reward via processes that might involve outputs to other regions (e.g., ventral pallidum). The other type of neuron expresses dopamine D1 receptors and dynorphin (Dyn). These neurons provide feedback regulation of the VTA; These neurons (orange) normally inhibit reward; DA binding at D1 receptors activates stimulatory G-proteins (Gs) and increases the activity of these neurons. Subsequent increases in DYN-induced stimulation of Gi-coupled KORs would tend to decrease the activity of VTA DA neurons. One consequence of this effect would be reduced D2 receptor function and increased inhibition of reward, causing hallmark signs of depression (e.g., anhedonia, dysphoria). According to this scheme, administration of KOR agonists would produce signs of depression by causing acute reductions in the activity of VTA neurons, whereas exposure to stress and drugs of abuse lead to CREB-regulated increases in DYN expression and more persistent behavioral effects. KOR antagonists might normalize the function of VTA neurons by preventing overstimulation of KORs, thereby producing antidepressant effects. For additional detail, see Carlezon and Thomas (2009). EndAlcohol Heroin Cocaine Amphetamine

Эндогенные лиганды опиоидных рецепторов Kieffer and Evans 2009

Dynorphin/KOR mediated Hedonic Processes before and after stress Dynorphin is one of the primary mediators of Anti-reward system mediates stress-induced behavior

Some of selective KOR antagonists Research Chemical LY2456302 Lilly

JDTic – NIDA News: The study was supported by the National Institute on Drug Abuse (NIDA), the National Institute of General Medical Sciences and the National Institute of Mental Health, all components of the National Institutes of Health. … NIDA Director Dr. Nora D. Volkow: “This research could aid in the development of effective medications for the treatment of drug addiction, particularly to stimulants like cocaine, for which there are no medications currently available. It may also be valuable for the development of safer pain medications.” This advance opens the door to the development of compounds targeting the KOR with improved therapeutic profiles Длительность блокады KOR после однократного введения JDTic животным составляет 56 дней

Nalmefene Naltrexone Naloxone Receptor Binding Affinity of Morphinans Compound Binding Affinity (nM) Agonist Efficacy [Emax] (%)1 MOR/KOR Ratio MOR KOR DOR Naltrexone1 0,4 2,0 12,5% 19,1 0,2 Nalmefene2 0,24 0,083 29% 16 ~3 Naloxone3 1,2 12 19 0,1 Buprenorphine4 0,52 0,47 1,17 ~1 1 Emmerson et al., Eur J Pharmacol. 2004 Jun 28;494(2-3):121-30. 2 Bart G et al. Neuropsychopharmacology. 2005 Dec;30(12):2254-62. 3 _Scientific_Discussion/human/000697/WC500058497.pdf 4 Villiger KW, Taylor KM.Life Sci.29, 2699–2708 (1981).

Доступные исследования каппа-антагонизма на людях (Buprenorphine + Naltrexone) Бупренорфин – мю-агонист, каппа-антагонист. Налтрексон - мю-антагонист Naltrexone and buprenorphine combination in the treatment of opioid dependence G. Gerra, A. Fantoma, National Department on Drug Policy, Rome, Italy A. Zaimovic Addiction Research Centre, Ser.T., AUSL, Parma, Italy J Psychopharmacol November 2006 vol. 20 no. 6 806-814 Results: Retention rate for 12 weeks (drug free urinalysis) Conclusion: Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.

Potential of Buprenorphine/Naltrexone in Treating Polydrug Addiction and Co- occurring Psychiatric Disorders DJ McCann Clinical Pharmacology & Therapeutics 83, 627-630 (April 2008) |doi:10.1038/sj.clpt.6100503 Conclusion: As we strive to address the needs of these complicated patients, studies of buprenorphine/naltrexone may hold the key to a major advance. Buprenorphine treatment of refractory depression Bodkin JA, Zornberg GL, Lukas SE, Cole JO McLean Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Belmont, MA 02178, USA. J Clin Psychopharmacol 1995 Feb; 15(1):49-57 Ten subjects with treatment-refractory, unipolar, nonpsychotic, major depression were treated with the opioid partial agonist buprenorphine in an open-label study. Results: seven subjects completed 4 to 6 weeks of treatment and showed clinically striking improvement in both subjective and objective measures of depression. Much of this improvement was observed by the end of 1 week of treatment and persisted throughout the trial. Four subjects achieved complete remission of symptoms by the end of the trial (Hamilton Rating Scale for Depression scores < or = 6), two were moderately improved, and one deteriorated. Доступные исследования каппа-антагонизма на людях

Search: “ALKS 5461” ALKS 5461 = samidorphan + buprenorphine selective µ-antagonist µ-agonist potent κ-antagonist

Search: “kappa” + “receptor”

Search: “kappa” + “receptor”

Search: “kappa” + “receptor”

Search: “kappa” + “receptor”

Standard preclinical studies did not accurately predict an apparent clinical toxicity of JDTic Kappa Therapeutics. Conference Program Book. CAMBRIDGE, MA, APRIL 24-27, 2013. p. 84 В РФ разработана и зарегистрирована депо-форма налоксона

Salvia divinorum (Шалфей предсказателей ) Salvinorin A potent κ-opioid receptor agonist самый мощный и селективный из известных KOR-агонистов S. divinorum is a psychoactive plant which can induce dissociative effects and is a potent producer of "visions" and other hallucinatory experiences. Salvinorin A is considered a dissociative exhibiting atypical psychedelic effects.

Dissociatives Dissociatives are a class of hallucinogens which reduce or block signals to enter the conscious mind from other parts of the brain. Tamminga, C. A.; Tanimoto, K., 1987 The most significant subjective difference between dissociatives and the classical hallucinogens (psychedelics such as LSD and mescaline) is the dissociative effect, including: depersonalization, the feeling of being disconnected from one's self, the feeling that the outside world is unreal, that it does not in fact exist (“near death experience”). Vollenweider, F; Geyer, MA (2001). "A systems model of altered consciousness: integrating natural and drug-induced psychoses". Brain Research Bulletin 56 (5): 495–507 Dissociation is a term in psychology describing phenomena of experiencing detachment from ones physical and emotional reality. In mild cases, dissociation can be regarded as a defense mechanism in seeking to minimize traumatic experience. Snyder, C.R., ed. (1999). Coping: The Psychology of What Works. Pathological dissociation involves dissociative disorders, including depersonalization disorder. The alterations in personal identity or sense of self can include: a sense that self or the world is unreal, psychological numbing, a loss of memory; forgetting identity or assuming a new self (fugue); and fragmentation of identity or self into separate streams of consciousness (dissociative identity disorder, formerly termed multiple personality disorder) and complex post-traumatic stress disorder. Kritchevsky M, Chang J, Squire LR (2004) A 2012 review article supports the hypothesis that current or recent trauma may affect an individual's assessment of the more distant past, changing the experience of the past and resulting in dissociative states. Stern DB (January 2012). "Witnessing across time: accessing the present from the past and the past from the present". The Psychoanalytic Quarterly 81 (1): 53–81

Depersonalization disorder symptoms are: • psychological and emotional numbing and anhedonia • inability to feel sorrow or happiness • loss of “sense of reality” and vitality • a sense of automation, going through the motions of life but not experiencing it or participating in it • inconstancy of identity • feeling disconnected from one's physicality Depersonalization disorder

…еще один тип реакции в клинике обозначается как деперсонализация или психическая анестезия. Защитная функция деперсонализации более очевидна, чем у остальных «регистров». Она возникает не только у больных, но и у здоровых людей после крайне сильной тревоги, вызванной острой стрессорной ситуацией: например, угрозой жизни, пытками, стихийными бедствиями, гибелью собственного ребенка и т.п. Биологические механизмы этой реакции связаны с эндорфинами и опиоидными рецепторами. Исходя из этого предположения, мы использовали для лечения больных деперсонализацией антагонист морфина — налоксон, блокирующий опиоидные рецепторы. Полученные положительные результаты, по-видимому, подтверждают правильность исходной гипотезы. Ю.Л.Нуллер, «Парадигмы в психиатрии», 1993 …перспективы терапии деперсонализации зависят от выявления ее патогенетических механизмов. Обнадеживающими являются положительные результаты использования блокатора опиатных рецепторов налоксона. По-видимому, препараты этой группы в скором времени окажутся эффективным методом лечения деперсонализации. …деперсонализация является мучительным состоянием, часто приводящим к суицидам… деперсонализация резко повышает терапевтическую резистентность тех психических расстройств, в рамках которых она возникает. Ю.Л.Нуллер, «Диагностика и терапия деперсонализационного расстройства» Ю.Л.Нуллер налоксон в терапии деперсонализационного расстройства

Treatment of refractory depression with an opiate antagonist and an antidepressant

Treatment of refractory depression with an opiate antagonist and an antidepressant

0 1 2 3 NTX NLM MOR KOR 29% 12,5% ФАРМАДИНАМИКА налтрексон и налмефен Ki (MOR/KOR)

ФАРМАКОКИНЕТИКА пероральный налтрексон Абсолютная биодоступность = 5% NTX Т1/2 = 4 ч 6β-NTX Т1/2 = 13 ч NTX Сmax = 8,6 нг/мл 6β-NTX С max = 99.3 нг/мл 6β-NTX / NTXСmax = 11,5

ФАРМАКОКИНЕТИКА VIVITROL Абсолютная биодоступность = 99% NTX Т1/2 = 5-10 дней 6β-NTX Т1/2 = 5-10 дней NTX / VIV AUC = 3-4

Возможные перспективы Вивитрола

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