Antinociceptive and Hypothermic Effects of Salvinorin A Are Abolished in a Novel Strain of κ-Opioid Receptor-1 Knockout Mice

Abstract

Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the -opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as -opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 g of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of -opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional -opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for 1 -but not 2 -opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for 1 -opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the -opioid receptor.

Kappa opioid receptor contributes to EGF-stimulated neurite extension in development

“…The observation that two axon extension markers were down-regulated in KOR-null spinal cord would suggest a functional role for KOR in EGF-stimulated axon extension. This was tested by using primary DRG neurons obtained from normal and KOR-null mutant mice (16), as well as normal and KOR-silenced primary rat DRG neurons. As shown in Fig.…”

“…To determine the physiological function of KOR in the developing nervous system, we conducted preliminary experiments using primary DRG neurons dissected from the wild-type (WT) and KOR-null animals (16) to examine several developmental parameters and the sensitivity of the dissected DRG cultures to stimulation by potential growth factors. Preliminary experiments suggested that, in developing embryos, KOR could play a functional role in neurite extension, particularly in response to EGF stimulation.…”

Selective Manipulation of Neural Circuits

“…To overcome this limitation, a new set of receptor and ligand was recently developed [152,153]. KORD, the new DREADD, is a kappa-opioid receptor coupled to inhibitory Gi protein and selectively responsive to an inert ligand, salvinorin B [153][154][155]. With 2 chemogenetic tools, the same circuit can be manipulated bidirectionally, activating or inactivating, with different ligands.…”

Salvia divinorum Epling & Játiva (Maria Pastora) e Salvinorina A: crescente uso recreacional e potencial de abuso

“…Esta substância parece ser "alucinógeno por excelência" (Valdes, 1994), produzindo efeitos psicotrópicos apenas pela estimulação do receptor opióide kappa (González et al, 2006;Prisinzano, 2005;Babu et al, 2008), com afinidade muito pouco significativa pelos receptores opióides mu (Wang et al, 2004;Rothman et al, 2007) e kappa do tipo 2 (Ansonoff et al, 2006) e sem ação sobre receptores serotoninérgicos do tipo 2A (González et al, 2006;Prisinzano, 2005;Babu et al, 2008).…”

“…A ativação de KOP in vivo causa analgesia, disforia, elevação corticoesteróide, diurese (Wang et al, 2004;Lee et al, 2005) e hipotermia (Ansonoff et al, 2006), porém não determina depressão respiratória (Babu et al, 2008).…”