Sex Difference in κ-Opioid Receptor (KOPR)-Mediated Behaviors, Brain Region KOPR Level and KOPR-Mediated Guanosine 5′-O-(3-[³⁵S]Thiotriphosphate) Binding in the Guinea Pig

Abstract

We examined whether sex differences in -opioid receptor (KOPR) pharmacology exist in guinea pigs, which are more similar to humans in the expression level and distribution of KOPR in the brain than rats and mice. The KOPR agonist trans-(Ϯ)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide methanesulfonate (U50,488H) produced a dose-dependent increase in abnormal postures and immobility with more effects in males than females. Males also showed more U50,488H-induced antinociception in the paw pressure test than females. Pretreatment with the KOPR antagonist norbinaltorphimine blocked U50,488H-induced abnormal body postures and antinociception. In contrast, inhibition of cocaine-induced hyperambulation by U50,488H was more effective in females than males. Thus, sex differences in the effects of U50,488H are endpoint-dependent. We then examined whether sex differences in KOPR levels and KOPR-mediated G protein activation in brain regions may contribute to the observed differences using quantitative in vitro autora-

κ-Opioid Receptors within the Nucleus Accumbens Shell Mediate Pair Bond Maintenance

“…However, consistent with other species, including humans (Mansour et al, 1987(Mansour et al, , 1988Quirion et al, 1987), there is dense -opioid receptor binding throughout the striatum. This distribution pattern is similar to that of other rodents (guinea pig, rabbit, mouse, and rat) that also show dense binding within the striatum (Robson et al, 1985;Wang et al, 2011).…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Moderate to high levels of dynorphin mRNA and κ opioid receptors are expressed in regions of the brain that are stress-related in rodents, including the hypothalamic paraventricular nucleus (PVN), amygdala (AMY), hippocampus (Hip) and bed nucleus of the stria terminalis (BNST) [11,26,27] , and stress exposure has been shown to increase endogenous dynorphin levels [28] . A growing body of evidence reveals that the dynorphin/κ opioid receptor system plays an important role in stress [29][30][31] .…”

“…Indeed, THC, a CB1 receptor agonist, microinjected at low doses in the prefrontal cortex and ventral hippocampus induced an anxiolytic-like response, while high doses caused an anxiogenic reaction [52] . Considering that κ opioid receptors are widely expressed in the central nervous system [11] , it is not surprising that specific brain regions (ie, prefrontal cortex, amygdala and hypothalamus) may have opposite and complementary roles in the regulation of anxiety by κ opioid receptors. Further studies are clearly needed to understand the mechanism involved in biphasic effects induced by κ opioid receptor agonists.…”

“…In the brain, κ opioid receptors are present primarily in the claustrum, cortex, hypothalamus, endopiriform nucleus, nucleus accumbens, caudate putamen, and substantial nigra [9][10][11] . Stimulation of κ opioid receptors results in the dissociation of G proteins into Gα and Gβγ subunits, in turn affecting a variety of effectors including adenylyl cyclase, potassium/calcium channels, phospholipase C and the p42/44 mitogen-activated protein kinase pathway [12] .…”

A cell-based, high-throughput homogeneous time-resolved fluorescence assay for the screening of potential κ-opioid receptor agonists

“…KOR is widely distributed in the central and peripheral nervous system and predominantly localized in the cerebral cortex, nucleus accumbens, claustrum and hypothalamus. KOR stimulation produces various physiological functions, such as analgesia, antipruritic activity, diuresis, stress, depression, drug abuse, anxiety and psychotic behaviors [6][7][8] . Therefore, KOR is rapidly emerging as an important target for the treatment of a variety of human disorders.…”