Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

Abstract

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.

Clinical applications of hallucinogens: A review.

“…However, concerns remain about safety and toxicity of ibogaine, tempering the widespread implementation of ibogaine research and treatment for the time being (Alper et al, 2012; Hoelen et al, 2009). Preclinical data and basic human research on Salvinorin A (SA) suggest an important role for the Kappa opioid receptor system in modulating addiction, mood, and consciousness (Addy et al, 2012; 2015; Freeman et al, 2014; Johnson et al, 2011; 2016); though clinical research has yet to provide evidence for therapeutic use of SA, which remains an important direction for future research (Butelman & Kreek, 2015; Chavkin, 2011). Cannabis and the cannabinoids have shown therapeutic value as a treatment for chronic pain, spasticity in multiple sclerosis, and chemotherapy induced nausea (Whiting et al, 2015), with a number of other conditions such as cancer, epilepsy, sleep disorders, and PTSD implicated as possible targets for cannabis-based treatments.…”

“…SA, in contrast, leads to conditioned place aversion and decreased intracranial self-stimulation (Carlezon et al, 2006; Sufka et al, 2014). Dynorphins, the endogenous ligands for the KOR have been implicated in many adverse behaviors including stress-induced drug relapse in animal models (Beardsley et al, 2005) and have been proposed as important therapeutic targets for addiction treatments (Butelman & Kreek, 2015; Chavkin, 2011;). SA may also have downstream effects on the endocannabinoid system (Braida et al, 2007; 2008), but this has not yet been demonstrated in primates.…”

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

“…Recent studies in animal models have revealed that Salvinorin A exerts a number of pharmacological actions of potential therapeutic interest which are not solely limited to the central nervous system (Butelman and Kreek, 2015). These include attenuation of inflammation (Aviello et al, 2011; Rossi et al, 2016), inhibition of intestinal motility (Capasso et al, 2008), and antipruritic effects (Salaga et al, 2015).…”

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

“…Compared with brain‐accessible agonists, the analgesic effects of peripherally restricted agonists are not accompanied by sedative effect, respiratory depression or abuse potential. However, when KOR agonists penetrate the brain, they cause hallucination, dysphoric effects and aversion . Second‐messenger studies suggest that the dysphoric effects of KOR agonists involve G protein‐coupled recruitment of β‐arrestin and activation of p38 MAPK (mitogen‐activated protein kinase), whereas the analgesic effect is independent of such downstream signalling .…”