Sexual dimorphism in endothelin-induced nociceptive priming in infant rats

Abstract

In humans, neonatal surgery results in a dermatome specific enhancement in pain sensitivity and increases opioid requirements across all dermatomes upon a second surgical insult. To examine the mechanisms by which neonatal injury leads to pain sensitization, our lab has developed a model in which administration of Endothelin-1 (ET-1) subcutaneous into the hindpaw of postnatal day 7 rats results in a nociceptive priming when followed by a second administration to ET-1 on postnatal day 11. ET-1 is an endogenous peptide released in response to tissue injury and disease. Our working hypothesis is that ET-1-induced priming occurs in a sex hormone dependent manner. To test this hypothesis we administered 3.3 nmoles of ET-1 or saline into the left plantar hindpaw on postnatal day 7 in male and female rats. On postnatal day 11, male and female rats were exposed to ET-1 for a second time in left plantar hindpaw, right plantar hindpaw or left plantar forepaw. In male rats, exposure to ET-1 on postnatal day 7 and 11 increased ET-1 induced nociception in the ipsilateral, contralateral, and forepaw as compared to animals exposed to ET-1 on postnatal day 11 only. In contrast, in female rats, exposure to ET-1 on postnatal day 7 and 11 decreased ET-1 induced nociception in the ipsilateral hindpaw as compared to animals exposed to ET-1 on postnatal day 11 only. There was no alteration in contralateral or forepaw nociception in females. ET-1 induced nociceptive priming was attenuated with administration of morphine at time of ET-1 first exposure. ET-1-induced priming is sexually dimorphic with males developing systemic sensitization and females developing a localized de-sensitization to subsequent ET-1 induced nociception. These findings suggest that further attention to sex in human infant pain studies may be warranted. (Grant support: National Institutes of Health 1R01DA023593.) In humans, neonatal surgery results in a dermatome specific enhancement in pain sensitivity and increases opioid requirements across all dermatomes upon a second surgical insult. To examine the mechanisms by which neonatal injury leads to pain sensitization, our lab has developed a model in which administration of Endothelin-1 (ET-1) subcutaneous into the hindpaw of postnatal day 7 rats results in a nociceptive priming when followed by a second administration to ET-1 on postnatal day 11. ET-1 is an endogenous peptide released in response to tissue injury and disease. Our working hypothesis is that ET-1-induced priming occurs in a sex hormone dependent manner. To test this hypothesis we administered 3.3 nmoles of ET-1 or saline into the left plantar hindpaw on postnatal day 7 in male and female rats. On postnatal day 11, male and female rats were exposed to ET-1 for a second time in left plantar hindpaw, right plantar hindpaw or left plantar forepaw. In male rats, exposure to ET-1 on postnatal day 7 and 11 increased ET-1 induced nociception in the ipsilateral, contralateral, and forepaw as compared to animals exposed to ET-1 on postnatal day 11 only. In contrast, in female rats, exposure to ET-1 on postnatal day 7 and 11 decreased ET-1 induced nociception in the ipsilateral hindpaw as compared to animals exposed to ET-1 on postnatal day 11 only. There was no alteration in contralateral or forepaw nociception in females. ET-1 induced nociceptive priming was attenuated with administration of morphine at time of ET-1 first exposure. ET-1-induced priming is sexually dimorphic with males developing systemic sensitization and females developing a localized de-sensitization to subsequent ET-1 induced nociception. These findings suggest that further attention to sex in human infant pain studies may be warranted. (Grant support: National Institutes of Health 1R01DA023593.)