Aromatization of androgens into estrogens reduces response latency to a noxious thermal stimulus in male quail

Abstract

We recently demonstrated the presence of estrogen synthase (aromatase) and of estrogen receptors in the dorsal horn (laminae I–II) throughout the rostrocaudal extent of the spinal cord in male and female Japanese quail. The spinal laminae I–II receive and process abundant sensory information elicited, among others, by acute noxious stimulation of the skin and resulting in rapid, reflex-like withdrawal behavior. In the present study, we demonstrate that systemic treatment with estradiol or testosterone markedly decreases the latency of the foot withdrawal in the hot water test. A simultaneous treatment with an aromatase inhibitor blocks the effects of testosterone demonstrating, hence, that they are mediated by a conversion of testosterone into an estrogen by aromatase. Furthermore, the testosterone- or estradiol-induced decrease in foot withdrawal latency is blocked by a treatment with the estradiol receptor antagonist, tamoxifen, indicating that the effects are largely mediated by the interaction of estradiol with estrogen receptors. Together, these data suggest that sex steroids modulate sensitivity to noxious stimuli possibly by a direct action at the level of the dorsal horn of the spinal cord.

Introduction

The enzyme aromatase catalyses the conversion of androgens (e.g., testosterone, T) into estrogens (e.g., 17β-estradiol, E2) in various tissues including the brain Flores et al., 1973, Goto and Fishman, 1977. In the brain, aromatase has been known for many years to be particularly concentrated in the preoptic area and in other limbic nuclei such as the nucleus of the stria terminalis and the amygdala Balthazart et al., 1990a, Balthazart et al., 1990b, Roselli et al., 1985. In addition, we recently demonstrated the presence of numerous aromatase-immunoreactive neurons throughout the entire rostrocaudal extent of the dorsal (sensory) horn of the spinal cord (mainly in laminae I–II and, to a lesser extent, III) in adult male and female Japanese quail and rats Evrard and Balthazart, 2001, Evrard et al., 2000. It has also been found that these laminae of the dorsal horn contain nuclear estrogen receptor of the alpha sub-type in Japanese quail and in rats Amandusson et al., 1995, Evrard and Balthazart, 2002a, Keefer et al., 1973 supporting the idea that locally formed estrogens could affect neural processes near their site of synthesis, at least in part through genomic actions.

In birds like in mammals, neurons in laminae I–II process nociceptive nerve impulses that are produced in the periphery (e.g., skin and viscera) by noxious stimuli (e.g., vigorous pinches, hot water) and that are conveyed to the spinal dorsal horn neurons through primary afferent fibers Butler and Hodos, 1996, Millan, 1999, Necker, 2000. Therefore, the demonstration of a local conversion of androgens into estrogens in laminae I–II suggests that locally produced estrogens could alter the processing of nociceptive nerve impulses and consequently regulate the response threshold or latency to a noxious stimulus Blomqvist, 2000, Evrard et al., 2000. Interestingly, in rodents and humans, both T and E2 have been previously shown to control nociceptive threshold and latency to noxious stimuli in males (T and E2) and females (E2) (Fillingim and Ness, 2000). However, it is not known whether the effect of T on nociception depends on the aromatization of the androgen into an estrogen and would therefore be affected by an inhibition of aromatase. During reproduction, the steroid control of nociception in rodents and humans is assumed to play a significant role in the integration of reproductively relevant stimuli such as vaginal stimulation (Komisaruk and Whipple, 2000). Moreover, from a clinical perspective, dysfunction of this control may be partly responsible of dyspareunia (painful intercourse), migraine, and other steroid-dependent pain conditions Bradshaw and Berkley, 2002, Fillingim and Ness, 2000, Klimek, 1999.

The measurement of the intensity or duration of a noxious stimulus (e.g., electric shock, high mechanical pressure, hot water) required to elicit a behavioral response (e.g., tail flick, paw licking, vocalizations) has been extensively used to assess the effects of spinal factors on nociception (Le Bars et al., 2001). In mammals, evidence for a control of nociception by T and E2 has been obtained mainly by this approach (Fillingim and Ness, 2000). We recently developed and validated a behavioral test (hot water test) to assess the impact of spinal aromatization on nociception in quail (Evrard and Balthazart, 2002b). In the present study, we used this test to analyze the chronic effects of sex steroids and of the aromatization of androgens into estrogens on the processing of nociceptive information in male quail.