Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model

Abstract

Since herkinorin is the first non-opioid mu agonist derived from salvinorin A that has the ability to induce cerebral vascular dilatation, we hypothesized that herkinorin could have similar vascular dilatation effect via the mu and kappa opioid receptors and the cAMP pathway. The binding affinities of herkinorin to kappa and mu opioid receptors were determined by in-vitro competition binding assays. The cerebral arteries were monitored in piglets equipped with a closed cranial window and the artery responses were recorded before and every 30 s after injection of artificial cerebrospinal fluid (CSF) in the presence or absence of the investigated drugs: herkinorion, norbinaltorphimine (NTP), a kappa opioid receptor antagonist, β-funaltrexamine (β-FNA), a mu opioid receptor antagonist, or Rp-8-Br-cAMPS (Rp-cAMPS), an inhibitor of protein kinase A (PKA). CSF samples were collected before and 10 min after herkinorin and NTP administration for the measurement of cAMP levels. Data were analyzed by repeated-measures analysis of variance. Our results show that herkinorin binds to both kappa and mu opioid receptors. Its vasodilation effect is totally abolished by NTP, but is not affected by β-FNA. The levels of cAMP in the CSF elevate after herkinorin administration, but are abolished with NTP administration. The cerebral vasodilative effect of herkinorin is also blunted by Rp-cAMPS. In conclusion, as a non-opioid kappa and mu opioid receptor agonist, herkinorin exhibits cerebral vascular dilatation effect. The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process.

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability

“…9 Further evaluation of 2 ’s interaction with MORs indicated that it was a functionally selective compound, as it activates MORs without promoting the recruitment of β-arrestin-2 or internalization of the receptor, both of which have been indicated to play a critical role in development of morphine-like side-effects. 10 Although 2 has proven to be a useful tool for probing MORs in vitro 10–11 and in vivo , 12 it lacks sufficient potency (EC 50 = 39.0 ± 4.0 nM at MOR) and selectivity (4-fold selective for MOR over KOR) for further exploration of more complex systems of pain and drug abuse. The utility of 2 is also limited by the fact that it is peripherally restricted, 12b and thus cannot be used to probe centrally mediated processes.…”

“…10 Although 2 has proven to be a useful tool for probing MORs in vitro 10–11 and in vivo , 12 it lacks sufficient potency (EC 50 = 39.0 ± 4.0 nM at MOR) and selectivity (4-fold selective for MOR over KOR) for further exploration of more complex systems of pain and drug abuse. The utility of 2 is also limited by the fact that it is peripherally restricted, 12b and thus cannot be used to probe centrally mediated processes.…”

Toxicity Assessment of Structurally Relevant Natural Products from Mexican Plants with Antinociceptive Activity

“…This compound, obtained and characterized for the first time in 1982 by Dr. Alfredo Ortega in the Institute of Chemistry at UNAM [1], is a psychotropic terpenoid found in the plant Salvia divinorum, an indigenous plant from southern Mexico. This molecule is the first known opioid ligand that is not an alkaloid given the fact that it bears no basic nitrogen atoms [2]. This outstanding discovery exemplifies the relevance of natural products and advocates for the exploration and analysis of other compounds of this type.…”

cPKCγ membrane translocation is involved in herkinorin-induced neuroprotection against cerebral ischemia/reperfusion injury in mice

“…As β-arrestin-2 is important for the development of morphine-induced tolerance, constipation and respiratory depression, herkinorin may be a promising therapeutic agent for the treatment of stroke with fewer adverse effects. Certain studies have investigated the antinociceptive properties and cerebral vasodilative effects of herkinorin; however, efforts have seldom been made to evaluate the neuroprotective action of this compound ( 22 , 23 ). The present study demonstrated that administration of herkinorin into I/R mice significantly reduced infarct volume and markedly improved the recovery of neurological function.…”