UC San Diego

With the emergence of the opioid epidemic, it is becoming increasingly important to understand the various off target effects caused by opioids. One such side effect is a decrease in sex steroid production, a phenomenon called opioid-induced hypogonadism (OIH). OIH can occur in both males and females and is thought to develop through opioid suppression of the hypothalamic-pituitary-gonadal (HPG) axis. Previous studies have shown the hypothalamus to be the main target of opioid action; however, the exact mechanism is still unknown. This paper aims to illustrate the function of the µ-opioid receptor (µOR) in gonadotropin-releasing hormone neurons of the hypothalamus and how that may relate to the development of OIH.

We have found that immortalized GnRH neurons (GT1-7 cells) express function µOR, allowing us to use GT1-7 cells as the ideal in vitro model to test for cellular changes in GnRH neurons after opioid exposure. Using a cAMP Response Element luciferase (CRE-luc) reporter vector to measure transcription, we were able to illustrate that isoproterenol (ISO) and forskolin (FSK) activate CRE-luc in a dose-dependent manner. After morphine treatment, we saw an attenuation of ISO and FSK-induced CRE-luc activation. In addition, overexpression of the µOR caused an enhanced inhibition of CRE-luc activation. These findings suggest that morphine may alter GnRH expression through µOR activation to induce OIH via altered CRE binding-incidence. In addition, we found that morphine pretreatment in vivo alters GnRH neuron responsiveness to KISS1, as measured via luteinizing hormone (LH) output, but morphine pretreatment does not change pituitary responsiveness to GnRH. In mutant mice, where µOR is selectively deleted from GnRH neurons, morphine pretreatment is unable to suppress KISS1 activation of GnRH neurons. These results suggest that µOR activation in GnRH neurons is needed for morphine-mediated suppression of the HPG axis. Furthermore, chronic morphine treatment in female mice did not significantly alter gene expression in the hypothalamus, pituitary, or ovaries. This illustrates that chronic morphine use may not permanently alter expression of key reproductive genes. Overall, these findings suggest that opioid action via the µOR in GnRH neurons plays a key role in the suppression of the HPG axis. Future studies must be conducted to fully define altered GnRH expression and secretion in the development of OIH.