Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons

Abstract

In addition to exerting genomic actions via nuclear receptors within hours to days, estrogens also regulate neuronal activity much faster (within seconds) by activating neuronal membrane receptors coupled to intracellular second-messenger pathways. To date, the origin of estrogens inducing rapid effects in the brain remains unclear, although it is often ascribed to the gonads. We report here that an acute blockade of the endogenous synthesis of estrogens in the quail spinal dorsal horn markedly reduced, within 1 min, the behavioral responsiveness to a thermal painful stimulus. Similar rapid effects in the opposite direction were induced by estradiol. This finding identifies a new paracrine and nongenomic mechanism for the regulation of pain by estrogens. Such regulation was assumed previously to result only from slow genomic actions of estrogens arising from the ovaries. Also, quite importantly, this finding suggests that the numerous rapid nongenomic effects of estrogens in the CNS could depend on their immediate local production by the enzyme aromatase, independently from the gonads.

Figure 1.

Peripheral treatment with an aromatase inhibitor or with E2 rapidly increases or decreases, respectively, withdrawal latency from a 54°C water bath. A, Foot-withdrawal latency in the hot water test in castrated subjects with empty, T-filled, or E2-filled subcutaneous implants 20 min after an intraperitoneal injection of vorozole or its vehicle. B, Foot-withdrawal latency in the same subjects 20 min after an intraperitoneal injection of E2 or its vehicle. Tukey's tests; ^$p < 0.01 and ^#p < 0.05 versus castrates submitted to the same acute treatment; ^*p < 0.01 versus vehicle-injected birds submitted to the same chronic treatment.

Figure 2.

Spinal aromatase inhibition results in a rapid increase of foot-withdrawal latency from a 54°C water bath; this effect is bypassed by E2. A-C, Latency in gonadally intact subjects before and 1, 5, and 30 min after an intrathecal (i.t.) injection of vorozole (A), ATD (B), or E2 (C) or after injection of the corresponding vehicle. D, Latency in gonadally intact subjects before and 1, 5, and 30 min after an intrathecal injection of vorozole alone or mixed with E2. E, Latency in gonadally intact subjects before and 1, 5, and 30 min after an intracerebroventricular (i.c.v.) injection of vorozole or its vehicle. Tukey's tests; ^*p < 0.01 versus 0 and 30 min after the same treatment; ^$p < 0.01 versus other condition after the same amount of time; ^#p < 0.05 versus 5 min after the same treatment.