Inflammation induced by endotoxin from Escherichia coli enables the central action of caffeine on GnRH/LH secretion in female sheep

Caffeine is considered to be the most utilized psychoactive stimulant worldwide. It easily crosses the blood-brain barrier and may antagonize adenosine receptors and activate ryanodine receptors in the brain. Administered peripherally, caffeine reduces inflammatory-associated changes in the secretory activity of the hypothalamic-pituitary unit, which regulates reproductive function in females. However, these effects of caffeine could result from both its central and peripheral actions. Therefore, the present study aimed to determine the influence of central injection of caffeine on the secretory activity of the hypothalamic-pituitary unit in ewes under basal conditions and inflammation induced by peripheral injection of endotoxin from Escherichia coli - lipopolysaccharide (LPS). Experiments were performed on 2-year-old ewes ( n = 24) in the follicular phase of the estrous cycle synchronized via the Chronogest ® CR method, 24 h after PMSG injection. Inflammation was induced by intravenous injection of LPS (400 ng/kg), whereas the control ewes received an equivalent volume of saline. An intracerebroventricular injection of caffeine (3 mg/animal) was performed through a steel guide cannula implanted into the third ventricle immediately after the LPS/saline treatment. Blood collection started two hours before experimental factor administration and continued for the next three hours. Then, the ewes were sacrificed, and the anterior pituitary and four hypothalamic structures involved in GnRHergic activity were dissected. Caffeine stimulated ( p < 0.05) the biosynthesis of gonadotropin-releasing hormone (GnRH) in the preoptic area (POA) of the hypothalamus only in LPS-treated ewes. Moreover, administration of caffeine did not affect basal luteinizing hormone (LH) secretion but abolished the inflammation-dependent decrease in LH secretion. This caffeine-mediated effect on GnRH/LH secretion may result from its anti-inflammatory action because caffeine injection decreased ( p < 0.05) the gene expression of tumor necrosis factor (TNF) α in the POA, as well as from changes in the concentration of GnRH in neuron terminals. Our study revealed that centrally acting caffeine may influence GnRH/LH secretion in ewes, depending on their physiological condition. A single central injection of caffeine in ewes treated with bacterial endotoxin abolished the inflammation-dependent decrease in GnRH/LH secretion but did not affect the hypothalamic-pituitary unit in healthy ewes.