Sex differences and the role of estrogen, estrous cycle, and DRG neurons in a mouse model of cancer pain

Abstract

While conflicting views exist in the literature regarding sex differences in cancer pain, recent studies show that women are more likely to experience greater cancer pain than men. Transient receptor potential (TRP) are considered critical receptors in tumor-induced peripheral sensitization while cycling sex steroid hormones are considered critical factors in sex-dependent differences in cancer pain. Whether sex differences in cancer pain are due to estrogens affect on TRP receptors has yet to be determined. Utilizing a mouse model of bone cancer, we compared tumor-induced mechanical allodynia and thermal (heat and cold) hyperalgesia in intact, gonadectomized, and estradiol-replaced males and females. Tumor-induced changes in TRP and estrogen receptor mRNA levels were assessed. We also examined the anti-nociceptive effects of a topical application of a TRPM8 agonist (menthol) and subcutaneous injected TRPV1 antagonist on tumor-induced nociception. We found no sex differences in tumor-induced mechanical allodynia, but, there was greater mechanical allodynia in females during proestrus/estrus than during diestrus. Estradiol replacement in gonadectomized females increased tumor-induced mechanical allodynia, but decreased allodynia in gonadectomized males. Collectively, females were more sensitive to tumor-induced cold hyperalgesia than males. Tumor-induced cold sensitivity was increased in all gonadectomized animals regardless of estradiol replacement. GPR30 mRNA was greater in females during diestrus than proestrus/estrus. TRPV1 mRNA was lower in diestrus females but greater during proestrus/estrus. Estradiol replacement had in inverse effect on TRPV1 mRNA expression in gonadectomized females, but had no effect in gonadectomized males. TRPM8 mRNA was greater in females than males, while TRPA1 mRNA was greater in males than in females. The TRPV1 antagonist induced antinociception in proestrus/estrus females, but this effect was reduced in estradiol replaced gonadectomized males. Menthol-induced antinociception was reduced in gonadectomized females, but restored with estradiol replacement. These findings suggest that estrogen mediates sex differences in tumor-induced mechanical allodynia and cold hyperalgesia, TRP expression, menthol-induced antinociception as well as TRPV1 antagonist antinociception. Collectively, this verifies that estrogen is, in part, responsible for contrasting sensitivity of males and females to cancer pain.