Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: a potential component of nociception.
A crucial biochemical reaction in vertebrates is progesterone conversion into neuroactive metabolites such as dihydroprogesterone (5alpha-DHP) and tetrahydroprogesterone (3alpha,5alpha-THP), which regulate several neurobiological processes, including stress, depression, neuroprotection, and analgesia. 3alpha,5alpha-THP is a potent stimulator of type A receptors of GABA, the main inhibitory neurotransmitter. Here, we show that in the spinal sensory circuit progesterone conversion into 5alpha-DHP and 3alpha,5alpha-THP is inhibited dose-dependently by substance P (SP), a major mediator of painful signals. We developed a triple-labeling approach coupled with multichannel confocal microscope analysis, which revealed that, in the spinal cord (SC), SP-releasing afferents project on sensory neurons expressing simultaneously neurokinin 1 receptors (rNK1) and key enzymes catalyzing progesterone metabolism. Evidence for a potent inhibitory effect of SP on 5alpha-DHP and 3alpha,5alpha-THP formation in the SC was provided by combining pulse-chase experiments using [3H]progesterone as precursor, HPLC, recrystallization of [3H]metabolites to constant specific activity, and continuous flow detection of radioactive steroids. The action of SP on progesterone metabolism was mimicked by the rNK1-specific agonist [Sar-9,Met(O2)11]-SP. The selective rNK1 antagonist SR140333 totally reversed the effect of SP on progesterone conversion into 5alpha-DHP and 3alpha,5alpha-THP. These results provide direct evidence for the occurrence of anatomical and functional interactions between the SP-rNK1 system and neuroactive steroid-producing cells in the SC. The data suggest that, through the local control of 3alpha,5alpha-THP concentration in spinal sensory circuit, the SP-rNK1 system may indirectly interfere with GABA(A) receptor activity in the modulation of nociceptive transmission.
Patte-Mensah
Christine
C
Laboratoire de Neurophysiologie Cellulaire et Intégrée, Unité Mixte de Recherche 7519, Centre National de la Recherche Scientifique, Université Louis Pasteur, 21 Rue René Descartes, 67084 Strasbourg Cedex, France.
Kibaly
Cherkaouia
C
Mensah-Nyagan
Ayikoe G
AG
D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D008959:Models, Neurological; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D013373:Substance P; D011374:Progesterone; D005680:gamma-Aminobutyric Acid