Effects of neonatal visceral pain on morphine tolerance, dependence, and withdrawal in rats

Abstract

Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but few studies have examined the impact of these changes on opioid pharmacology. In these studies, we examined the effects of NVP on the development of tolerance, dependence, and expression of withdrawal effects of morphine in the rat. Experimental rats were subjected to a colorectal distension procedure on postnatal days 4, 6, and 8 to induce NVP, while control rats were not exposed to the NVP procedure. All rats were gradually shaped to a terminal FR20 schedule reinforced by food presentation. Once responding was stable and reliable, saline was injected subcutaneously (SC) before behavioral sessions, and morphine was administered (SC) immediately after behavioral sessions. Morphine doses were increased one quarter‐log every 7 days, from 1.0 mg/kg, to a final dose of 30 mg/kg, upon which rats were maintained for the duration of the experiment. Various doses of the opioid antagonist naltrexone (NTX) were sometimes administered 10 min before behavioral sessions to precipitate withdrawal. For both groups of rats, NTX dose‐dependently suppressed response rates, indicative of a precipitated withdrawal effect on food‐maintained responding. However, NTX induced more pronounced rate suppression in NVP rats at all tested doses. These findings demonstrate that the changes in brain opioid systems elicited by NVP have persistent pharmacological consequences into adulthood, are consistent with our previous studies suggesting that NVP increases sensitivity to abuse‐related effects of opioids across development, and extend our characterization of this vulnerable phenotype to include an increased susceptibility to antagonist‐precipitated withdrawal. These studies supported by the UAMS Center for Translational Neuroscience (RR020146) and the UAMS Translational Research Institute (RR029884).