Neonatal and Adult Gonadal Hormone Manipulations Enhance Morphine Analgesia Elicited from the Ventrolateral Periaqueductal Gray in Female Rats

Abstract

Male rodents displayed greater magnitudes of analgesia following systemic, ventricular, and intracerebral administration of mu-opioid receptor agonists than female rodents. Whereas neonatal castration of male rat pups produced reductions in systemic and central morphine analgesia as adults, neonatal androgenization of female rat pups treated with testosterone propionate (TP) displayed enhancements in systemic and central morphine analgesia as adults. Adult gonadectomy minimally affected mu-opioid analgesia, except if less potent mu agonists were employed, or if morphine was directly administered into the ventrolateral periaqueductal gray (vlPAG). Adult ovariectomy failed to appreciably alter the enhanced analgesia following systemic morphine in female rats with neonatal androgenization. Because the vlPAG elicited morphine analgesia that was sensitive to both neonatal and adult gonadal hormone manipulations, the present study examined morphine analgesia elicited from the vlPAG in female rats receiving neonatal treatment with TP or vehicle and subsequently exposed to adult ovariectomy or sham surgery as well as intact male rats. Intact male rats displayed significantly greater magnitudes and potencies in vlPAG morphine analgesia than female rats receiving neonatal treatment with either vehicle or TP. In turn, neonatal androgenization significantly enhanced vlPAG morphine analgesia relative to neonatal vehicle treatment in females. Adult ovariectomy significantly enhanced the magnitude of vlPAG morphine analgesia in female rats receiving neonatal treatment with either vehicle or TP. This demonstrates a strong interaction between neonatal and adult gonadal hormone manipulations in the mediation of vlPAG morphine analgesia in female rats.

A novel use for testosterone to treat central sensitization of chronic pain in fibromyalgia patients

“…Other sites within the nociceptive system appear to be important as well: androgen and estrogen receptors have also been localized to midbrain PAG neurons projecting to the medullary RVM in male and female rats [39][40][41], as well as male primates [42]; and the male rat locus coeruleus, an important site in the pons for brain synthesis of noradrenaline and involved in descending pain inhibition pathways, has also been found to be androgen receptor positive [39]. Neonatal castration of male rat pups was found to result in reduced analgesia in adults when morphine was injected into the PAG, and neonatal androgenization of female rat pups treated with testosterone propionate resulted in enhanced PAG morphine analgesia as adults [43,44].…”

The role of gonadal hormones in regulating opioid antinociception

“…The ventrolateral periaqueductal gray (vlPAG) may be a site at which TT interacts with opioids to regulate pain inhibition. The analgesic effect of morphine via microinjection into the vlPAG was reduced among castrated male rats, while in androgenized female rats, the analgesic efficacy was enhanced [ 70 ].…”