Inhibiting Kiss1 Neurons With Kappa Opioid Receptor Agonists to Treat Polycystic Ovary Syndrome and Vasomotor Symptoms

Abstract

Context Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons). Objective We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally-restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood brain barrier) and impedes their down-stream effects. Design Case/control. Setting Academic medical center. Participants Mice. Interventions Administration of peripherally-restricted kappa receptor agonists and frequent blood sampling to determine hormone release, and body temperature. Main Outcome Measures LH pulse parameters and body temperature. Results First, chronic administration of a PRKA to OVX mice with experimentally-induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity. Conclusion The inhibition of Kiss1 neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Invited review: Translating kisspeptin and neurokinin B biology into new therapies for reproductive health

“…95 In this study, inhibition of kisspeptin neuronal activity by chronic administration of kappa opioid receptor agonists to bilaterally ovariectomised mice with experimentally induced hyperactivity of KNDy neurons significantly reduced the elevated body temperature. 95 Taken together, this series of preclinical experiments emphasises the importance of KNDy neurons in the generation of hot flushes, as well as the promise of targeting these neurons to treat vasomotor symptoms.…”

“…Moreover, a very recent study examined the effects of administration of a peripherally restricted kappa receptor agonist (which can access brain areas including the ARC via the fenestrated capillaries of the median eminence) on vasomotor symptoms 95 . In this study, inhibition of kisspeptin neuronal activity by chronic administration of kappa opioid receptor agonists to bilaterally ovariectomised mice with experimentally induced hyperactivity of KNDy neurons significantly reduced the elevated body temperature 95 . Taken together, this series of preclinical experiments emphasises the importance of KNDy neurons in the generation of hot flushes, as well as the promise of targeting these neurons to treat vasomotor symptoms.…”

“…Conversely, pre‐treatment with a cocktail of neurokinin receptor antagonists (given that NKB has a degree of affinity for all three neurokinin receptors) delivered to the preoptic area prevented the increase in tail‐skin temperature following activation of ARC kisspeptin neurons 94 . Moreover, a very recent study examined the effects of administration of a peripherally restricted kappa receptor agonist (which can access brain areas including the ARC via the fenestrated capillaries of the median eminence) on vasomotor symptoms 95 . In this study, inhibition of kisspeptin neuronal activity by chronic administration of kappa opioid receptor agonists to bilaterally ovariectomised mice with experimentally induced hyperactivity of KNDy neurons significantly reduced the elevated body temperature 95 .…”

The role of gonadotropin‐releasing hormone neurons in polycystic ovary syndrome

“…Taken together, these studies suggest that the opioid signaling component of the KNDy pathway may be involved in PCOS pathophysiology and may be an important therapeutic target. Indeed, a recent preclinical study in PNA mice suggests that the KOR agonist difelikefalin, which does not cross the blood–brain barrier but still has access to regions near the fenestrated capillaries of the median eminence, ameliorates estrous cyclicity in addition to reducing serum testosterone 144 . Such results in an animal model with PCOS‐like features suggest that KOR agonists deserve further study as potential pharmacological agents for PCOS.…”

Impaired steroid hormone feedback in polycystic ovary syndrome: Evidence from preclinical models for abnormalities within central circuits controlling fertility

“…In a recent example of this strategy, Navarro and colleagues 70 demonstrated that peripherally restricted KOR agonists reduce the magnitude of LH pulse secretion in pDHT mice, while reducing testosterone levels and restoring cyclicity and ovulation. 70 The development of peripherally restricted drugs may therefore specifically target cells controlling fertility without adversely affecting other brain systems that control cognition, mood and other higher-order functions. This provides a promising avenue for the development of future therapeutic treatments in PCOS.…”