Effects of Unsaturated Fatty Acid Esters of Testosterone on Neuronal, Behavioral and Hormonal Parameters in Male Rats Subjected to the Formalin Test

Chronic diseases are often accompanied by inflammatory and degenerative processes. Estrogens have repeatedly been found to be involved in these processes. Testosterone (T) is the main precursor of estrogen in the brain and T replacement in chronic diseases has become important in recent years, prompting research on new T-conjugated molecules. We recently synthesized three new molecules including unsaturated fatty acid esters: T-linoleate (TL), T-oleate (TO) and T-eicosapentanoate (TEPA). These substances were s.c. administered for 7 days to intact male rats subjected to the formalin test (FT). Three other groups were included as comparisons: NAIVE, receiving no substance, OIL, treated with almond oil (vehicle), and TN, treated with T-undecanoate, a saturated fatty acid. Spontaneous behaviors and pain-induced responses were determined during the FT, hormones (T and dihydrotestosterone, DHT) were determined in blood, while estrogen receptors (ERα and β) were detected at the genomic and proteomic levels in the hippocampus, hypothalamus and spinal cord. In the hippocampus, ERα and ERβ mRNA levels were increased respectively by TN and TL treatments with respect to OIL, whereas the hypothalamus TO and TL caused a decrease of ERα mRNA levels. At the proteomic level, TO, TL and TEPA decreased the levels of ERα in the hypothalamus, whereas TEPA decreased ERβ in the spinal cord, hippocampus and hypothalamus. There was no effect of treatment on the spontaneous behaviors, while the TO and TL groups showed lower pain-induced behaviors (paw jerk frequency and licking duration) than the OIL group. TN increased paw jerk frequency and decreased licking duration with respect toOIL. The treatments had no effect on T and DHT plasma levels. These results clearly indicate the possibility of pain and ER modulation by T-esters.