Discovery of κ Opioid Receptor (KOR)-Selective <scp>d</scp>-Tetrapeptides with Improved <i>In Vivo</i> Antinociceptive Effect after Peripheral Administration

Alzheimer’s disease (AD) is a complex neurological disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles. Long term investigation of AD pathogenesis suggests that β-site amyloid precursor protein [APP] cleaving enzyme 1 (BACE1) and γ-secretase enzymes promote the amyloidogenic pathway and produce toxic Aβ peptides that are predisposed to aggregate in the brain. Hence, the targeted inhibition of BACE1/γ-secretase expression and function is a promising approach for AD therapy. Several reports have suggested that the opioid family of G-protein coupled receptors modulate the etiology of AD progression. It has also been found that changes in the signaling pathways of opioid receptors increased the expression of BACE1 and γ-secretase, and is strongly correlated with abnormal production of Aβ and pathogenesis of AD. Thus, the opioid receptor family is a promising candidate for targeted drug development to treat AD. In this review, we outline the involvement and mechanisms of opioid receptor signaling modulation in Alzheimer’s Disease progression.

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Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata

West

Holleran

2023

IJMS

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The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

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Discovery of κ Opioid Receptor (KOR)-Selective d-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration

Cited by 3 publications

References 30 publications

Targeting sensory neuron GPCRs for peripheral neuropathic pain

Targeting sensory neuron GPCRs for peripheral neuropathic pain

The role of opioid receptors in modulating Alzheimer’s Disease

Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata

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