Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: New concepts in mu opioid receptor pharmacology: From a symposium on new concepts in mu-opioid pharmacology

Abstract

Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin’s antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states.

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

“…In an inflammatory pain model in rat, herkinorin reduces formalin-induced flinching to the same degree as morphine when administered at the same dose (10 mg/kg, i.pl. ), an effect that is reversed by the opioid antagonist naloxone (Lamb et al 2012). Moreover, antinociceptive tolerance to herkinorin does not develop to repeated treatment over a 5-day period and it produces antinociception in morphine-tolerant rats (Lamb et al 2012).…”

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways

“…For instance, the MOR-selective ligand herkinorin from the atypical salvinorin A diterpenoid scaffold, which is fully efficacious as a MOR agonist at the G protein pathway and does not promote the recruitment of β -arrestin2 or induce receptor internalization, 14 has been reported to produce peripheral antinociception with decreased tolerance liability in rats. 15 More recently, structure-based optimization of a novel chemical scaffold identified by virtual screening led to the discovery of PZM21, another selective, atypical MOR agonist that preferentially activates the G i signaling pathway over β -arrestin2. 16 In vivo studies demonstrated that this compound is an efficacious analgesic that does not exhibit respiratory depression or morphine-like reinforcing activity at equianalgesic doses in mice.…”

Differential Potencies for Endogenous Dynorphins Indicate Functional Selectivity at the Delta Opioid Receptor

“…Upon activation -arrestin and Gi/o induce downstream signaling responses such as reduced cAMP levels. Recent drug discovery efforts identified several functionally selective exogenous opiates which prefer certain signaling pathways at a given receptorsuch as G stimulation -to others -such as -arrestin recruitment and generate desired pharmacological properties [3,4]. Noting that most of the 20+ endogenous opioid peptides are nonselective and some opiates display functional selectivity, two important points emerge.…”

“…Classically, ORs couple inhibitory Gi/o proteins and recruit -arrestin -a multifaceted scaffold molecule implicated in opioid mediated effects including tolerance, constipation, dysphoria and naseua [1,2]. Upon activation -arrestin and Gi/o induce downstream signaling responses such as reduced cAMP levels.…”

“…Second, two different endogenous opioid peptides may differentially activate a given receptor. Dynorphin A (DynA) and Dynorphin B (DynB) are considered OR agonists, despite binding to the OR at 1.29nM and 3.39 nM [1], respectively. The Dynorphins start with the 5 amino acid Leuenkephalin (Leu-Enk) sequence -YGGFL -traditionally considered a OR agonist followed by distinct C-terminal sequences.…”