Attenuation of inflammatory pain and facilitation of morphine-induced analgesia by testosterone: Organizational and activational effects.

摘要

Many painful conditions in humans such as rheumatoid arthritis have a higher incidence in women than in men. Furthermore, research examining gender differences in pain indicates that males typically have higher pain thresholds than females. Therefore, hormones may be involved in modulating nociceptive processes and more specifically testosterone may have a neuroprotective role in pain. The mechanism(s) by which gonadal hormones modulate nociceptive processes is still largely unknown although millions of individuals suffering from chronic pain could benefit from new treatments that would specifically target each gender. This study tested whether changes in the male hormonal milieu early or late in development alter the inflammatory pain induced by carrageenan (CARR, 3%, i.a.). Male rats were either castrated or sham castrated neonatally. Once they reached adulthood, males were either castrated or sham castrated, and received a testosterone or oil implant. After baseline testing two weeks later, a subcutaneous injection of saline, 1 mg/kg, or 5 mg/kg morphine was administered and animals were tested in response to mechanical and thermal stimulation following inflammation. Hormone alterations did not affect baseline responses, but CARR induced mechanical and thermal hypersensitivity in the injured paw. Castration in adult males injected with saline further increased sensitivity to mechanical but not thermal stimulation that was reversed by testosterone. Males castrated neonatally and injected with saline displayed lower mechanical threshold than control animals but this effect was not reversed by testosterone. Both doses of morphine increased mechanical and thermal thresholds. However, compared to the control group, 1 mg/kg morphine was equally effective in reducing mechanical hypersensitivity in animals castrated as adults, but less effective in males castrated neonatally apart from the type of implant. The results indicate that the neuroprotective role of testosterone in CARR-induced inflammation is established during development and maintained by circulating levels of testosterone in adulthood. The fact that depletion of testosterone in adulthood does not alter morphine potency, but depletion at birth does, suggests that the nociception-related interaction between the opioid system and testosterone is formed during the period of sexual differentiation.