PROGESTERONE-MEDIATED POTENTIATION OF SPINAL SUFENTANIL IN RATS

Pregnancy is associated with an increased sensitivity to both general and local anesthetics. The exact reason is uncertain, but increased concentrations of progesterone and endogenous opiates have been implicated. Therefore, we tested the ability of intrathecally administered progesterone to produce analgesia and to potentiate the effects of spinal sufentanil. Female rats had intrathecal catheters implanted for drug administration, and analgesia was measured using the tail flick assay or hemostat clamp test. Animals were pretreated first with 10 mug, 20 mug, or 40 mug of intrathecal progesterone (n = 5, for each dose) and then given a minimally analgesic dose of sufentanil. Pretreatment with progesterone potentiated sufentanil's effect and resulted in almost complete analgesia. In contrast, in animals not pretreated with progesterone, the same dose of sufentanil resulted in minimal analgesia (n = 15). Intrathecal progesterone alone had no analgesic effects. No behavioral or motor effects were noted after progesterone treatment. Cerebral spinal fluid progesterone levels were within physiologic range. Furthermore, 100 mug of progesterone administered intramuscularly did not potentiate sufentanil analgesia. A major progesterone metabolite, 5alpha-pregnane-3alpha-ol-20-one, 5 mug, 10 mug, or 20 mug (n = 5, for each dose), also potentiated sufentanil analgesia when administered intrathecally. In contrast, a stereoisomer, 5beta-pregnane-3beta-ol-20-one failed to show potentiation. Finally, two drugs that block gamma-aminobutyric acid-mediated increases in chloride ion conductance, picrotoxin and bicuculline, each blocked progesterone-mediated potentiation of sufentanil analgesia. These results demonstrate that intrathecal progesterone potentiates the analgesic effects of neuraxial opiates. Increased progesterone levels during pregnancy may potentiate the analgesic effect of endogenous opiates and may help, in part, to explain the decreased anesthetic requirements in these patients.