title: κ Agonists as a novel therapy for menopausal hot flashes.
abstract: OBJECTIVE
  The etiology of postmenopausal hot flashes is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing kisspeptin, neurokinin B and dynorphin-called KNDy neurons-are located adjacent to the thermoregulatory center. KNDy neurons regulate pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Dynorphin may inhibit this system by binding κ opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation.
  
  
  METHODS
  A double-blind, cross-over, placebo-controlled pilot study evaluated the effects of a κ agonist. Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate to severe hot flashes (aged 48-60 y) were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all three interventions: placebo, standard-dose pentazocine/naloxone (50/0.5 mg), or low-dose pentazocine/naloxone (25/0.25 mg). In an inpatient research setting, each participant received the three interventions, in randomized order, on three separate days. On each day, an intravenous catheter was inserted for LH blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded.
  
  
  RESULTS
  The mean (SEM) hot flash frequency 2 to 7 hours after therapy initiation was lower than that for placebo (standard-dose κ agonist, 4.75 [0.67] hot flashes per 5 h; low-dose κ agonist, 4.50 [0.57] hot flashes per 5 h; placebo, 5.94 [0.78] hot flashes per 5 h; P = 0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some--but not all--women.
  
  
  CONCLUSIONS
  This pilot study suggests that κ agonists may affect menopausal vasomotor symptoms.
authors.affiliation: 1Department of Physiology and Biophysics, University of Washington, Seattle, WA 2Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 3Department of Pharmacology, University of Washington, Seattle, WA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Oakley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Steiner
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
authors.forename: Donald K
authors.initials: DK
authors.lastname: Clifton
authors.forename: Laura K
authors.initials: LK
authors.lastname: Ferrara
authors.forename: Susan D
authors.initials: SD
authors.lastname: Reed
mesh_terms: D000701:Analgesics, Opioid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004399:Dynorphins / Q000096:biosynthesis; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D019584:Hot Flashes / Q000188:drug therapy*; D006801:Humans; D059648:Kisspeptins / Q000096:biosynthesis; D007986:Luteinizing Hormone / Q000378:metabolism; D008875:Middle Aged; D015287:Neurokinin B / Q000096:biosynthesis; D009474:Neurons / Q000502:physiology; D010423:Pentazocine / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D017698:Postmenopause; D017473:Receptors, Opioid, kappa / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; D059648:Kisspeptins; D010919:Placebos; D017473:Receptors, Opioid, kappa; D007987:Gonadotropin-Releasing Hormone; D004399:Dynorphins; D015287:Neurokinin B; D007986:Luteinizing Hormone; D010423:Pentazocine