Acute intermittent hypoxia (AIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Exposure to repetitive daily AIH (dAIH) enhances pLTF, a form of metaplasticity. Little is known concerning cellular mechanisms giving rise to dAIH-induced metaplasticity and the age-dependent sexual dimorphism of AIH associated pro-plasticity mRNA expression. To test if age, sex, and dAIH effects are associated with differential expression of molecules that regulate the Q- and S-pathways and their cross-talk interactions to phrenic motor facilitation, we analyzed key regulatory molecules in ventral spinal (C3-C5) homogenates from young (3-month) and middle-aged (12-month) male and female Sprague-Dawley rats. Since CNS estrogen levels impact molecules known to regulate the Q- and S-pathways, mRNA was correlated with serum estradiol. Rats (n = 8/group) were exposed to sham (21 % O2) or dAIH (15, 1 min episodes of 10.5 % inspired O2) per day for 14 days and sacrificed 24 h later. mRNAs for pLTF regulating molecules were assessed via RT-PCR, including: brain-derived neurotrophic factor (Bdnf); serotonin 2 A (Htr2a), 2B (Htr2b), and 7 (Htr7) receptors; adenosine 2a (Adora2a) receptors; exchange protein activated by cAMP (Epac1); p38 MAP kinase [Mapk14 (α) & Mapk11 (β)]; PKA regulatory (Prkar1a) and; catalytic subunits (Prkaa1); fractalkine (Cx3cl1), which underlies motor neuron/microglia communication; phosphodiesterase type 4b (Pde4b); NAPDH– gp91 (Cybb) and p47 (ncf1); and the PKC isoform, PKCδ (Prkcd). Here we report that age, sex, dAIH preconditioning, and estradiol influence molecules that initiate and/or regulate the Q- and S-pathways to phrenic motor facilitation.