The Therapeutic Potential of Novel Kappa Opioid Receptor-based Treatments

Introduction: Similarly to the μ opioid receptor, kappa opioid receptor (KOR), is present either in the central nervous system or in peripheral tissues. In the last years, several molecules, able to interact with KOR, have been the focus of basic research for their therapeutic potential in the field of chronic pain, as well as in depression, autoimmune disorders and neurological diseases. Discussion: The role of KOR system and the consequent clinical effects derived by its activation or inhibition are discussed. Their potential therapeutic utilization in conditions of stress and drug relapse, besides chronic pain, is presented here, including the possible use of KORagonists in drug addiction. Moreover, the potential role of KOR-antagonists, KOR agonistantagonists and peripheral KOR agonists is proposed. Conclusion: Other than pain, KORs have a role in regulating reward and mood. Due to its location, KORs seem to mediate interactions between psychiatric disorders, addiction and depression. Experimental studies in animal models have identified brain mechanisms that may contribute to clarify specific pathophysiological processes.

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The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach

10.1007/164_2020_396 ◽

2020 ◽

Author(s):

Samuel David Clark

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Healthy Volunteers ◽

Opioid Receptor ◽

Clinical Data ◽

Potential Role ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Major Depressive

AbstractThe kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders. This review covers a brief history of the development of KOR agonists and antagonists, their effects in healthy volunteers, and the potential role of DYN/KOR dysfunction in schizophrenia and major depressive disorder from a translational perspective. The potential role of DYN/KOR dysfunction in schizophrenia is based on several lines of evidence. Selective KOR agonists induce affective states in healthy volunteers with similarities to the symptoms of schizophrenia. Studies have shown increased DYN in patients with schizophrenia, although the data have been mixed. Finally, meta-analytic data have shown that opioid antagonists are associated with reductions in the symptoms of schizophrenia. The potential role of DYN/KOR dysfunction in major depressive disorder is also based on a combination of preclinical and clinical data. Selective KOR agonists have shown pro-depressive effects in human volunteers, while selective KOR antagonists have shown robust efficacy in several preclinical models of antidepressant activity. Small studies have shown that nonselective KOR antagonists may have efficacy in treatment-resistant depression. Additionally, recent clinical data have shown that the KOR may be an effective target for treating anhedonia, a finding relevant to both schizophrenia and depression. Finally, recommendations are provided for translating preclinical models for schizophrenia and major depressive disorder into the clinic.

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Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

Neuropharmacology ◽

10.1016/j.neuropharm.2015.08.027 ◽

2015 ◽

Vol 99 ◽

pp. 600-609 ◽

Cited By ~ 16

Author(s):

Jenny Morgenweck ◽

Kevin J. Frankowski ◽

Thomas E. Prisinzano ◽

Jeffrey Aubé ◽

Laura M. Bohn

Keyword(s):

Mouse Model ◽

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Receptor Modulation

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Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

10.1101/2020.04.24.059352 ◽

2020 ◽

Author(s):

Elyssa B. Margolis ◽

Tanya L. Wallace ◽

Lori Jean Van Orden ◽

William J. Martin

Keyword(s):

Opioid Receptor ◽

Therapeutic Potential ◽

Outward Current ◽

Complete Recovery ◽

Kappa Opioid Receptor ◽

Dopamine Neurons ◽

Kappa Opioid ◽

Opioid Receptor Antagonists ◽

Neurobehavioral Disorders ◽

Circuit Function

AbstractActivation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively). JNJ-67953964 showed an IC50 of 0.3 ± 1.3 nM. PF-04455242 (IC50 = 19.6 ± 16 nM) exhibited partial antagonist activity (∼60% maximal blockade). In 50% of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within disorder-relevant circuits implicated in neurobehavioral disorders.

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Participation of opioid receptors in the cytoprotective effect of chronic normobaric hypoxia

Physiological Research ◽

10.33549/physiolres.933938 ◽

2019 ◽

pp. 245-253 ◽

Cited By ~ 4

Author(s):

N.V. Naryzhnaya ◽

I. Khaliulin ◽

Y.B. Lishmanov ◽

M.S. Suleiman ◽

S.Y. Tsibulnikov ◽

...

Keyword(s):

Cell Death ◽

Lactate Dehydrogenase ◽

Opioid Receptor ◽

Kappa Opioid Receptor ◽

Normobaric Hypoxia ◽

Cytoprotective Effect ◽

Kappa Opioid ◽

Isolated Cardiomyocytes ◽

Ldh Release

We studied the role of the delta, micro, and kappa opioid receptor (OR) subtypes in the cardioprotective effect of chronic continuous normobaric hypoxia (CNH) in the model of acuteanoxia-reoxygenation of isolated cardiomyocytes. Adaptation of rats to CNH was performed by their exposure to atmosphere containing 12% of O(2) for 21 days. Anoxia-reoxygenation of cardiomyocytes isolated from normoxiccontrol rats caused the death of 51 % of cells and lactate dehydrogenase (LDH) release. Adaptation of rats to CNH resulted in the anoxia/reoxygenation-induced cardiomyocyte death of only 38 %, and reduced the LDH release by 25 %. Pre-incubation of the cells with either the non-selective OR (opioid receptor) blocker naloxone (300 nM/l), the delta OR antagonist TIPP(psi) (30 nM/l), the selective delta(2) OR antagonist naltriben (1 nM/l) or the micro OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia abolished the reduction of cell death and LDH release afforded by CNH. The antagonist of delta(1) OR BNTX (1 nM/l) or the kappa OR antagonist nor-binaltorphimine (3 nM/l) did not influence the cytoprotective effects of CNH. Taken together, the cytoprotective effect of CNH is associated with the activation of the delta(2) and micro OR localized on cardiomyocytes.

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Modulation of Cocaine-induced Sensitization by kappa-Opioid Receptor Agonists: Role of the Nucleus Accumbens and Medial Prefrontal Cortex

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1999.tb09327.x ◽

1999 ◽

Vol 877 (1 ADVANCING FRO) ◽

pp. 803-806 ◽

Cited By ~ 10

Author(s):

VLADIMIR CHEFER ◽

ALEXIS C. THOMPSON ◽

TONI S. SHIPPENBERG

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Opioid Receptor ◽

Medial Prefrontal Cortex ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Receptor Agonists ◽

Opioid Receptor Agonists

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The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain

European Journal of Pharmacology ◽

10.1016/j.ejphar.2011.09.169 ◽

2011 ◽

Vol 671 (1-3) ◽

pp. 53-60 ◽

Cited By ~ 8

Author(s):

Yaeko Tsukahara-Ohsumi ◽

Fumio Tsuji ◽

Masashi Niwa ◽

Taeko Hata ◽

Minoru Narita ◽

...

Keyword(s):

Chronic Pain ◽

Opioid Receptor ◽

Receptor Agonist ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Opioid Receptor Agonist ◽

Sedative Effects

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Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

PLoS ONE ◽

10.1371/journal.pone.0232864 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0232864

Author(s):

Elyssa B. Margolis ◽

Tanya L. Wallace ◽

Lori Jean Van Orden ◽

William J. Martin

Keyword(s):

Opioid Receptor ◽

Therapeutic Potential ◽

Outward Current ◽

Complete Recovery ◽

Kappa Opioid Receptor ◽

Dopamine Neurons ◽

Kappa Opioid ◽

Opioid Receptor Antagonists ◽

Neurobehavioral Disorders ◽

Circuit Function

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.

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