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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.

Substance P inhibits progesterone conversion to neuroactive metabolites in spinal sensory circuit: A potential component of nociception