Long‐term effect of morphine administration in young rats on the analgesic opioid response in adult life

Abstract

Neonates, infants and children are often exposed to pain from invasive procedures during intensive care and during the post-operative period. Opioid anesthesia and post-operative opioid analgesia have been used in infants and result in clinical benefits. The objectives of this study were to verify the effect of repeated 5 microg morphine administration (subcutaneous), once a day for 7 days in 8-day-old rats, at P8 until P14. To verify the long-term effect of morphine, the animals were submitted to a second exposure of 5mg/kg (intraperitoneal) of morphine at P80 until P86. Animals that received morphine for 7 days, at P14 did not develop tolerance, however at P80, rats demonstrated greater morphine analgesia. At P86, after 7 days of morphine administration, animals showed classical tolerance. These findings may have important implications for the human neonate, suggesting a possible explanation for the differences in the requirements of morphine observed in the youngest patients.

Maternal deprivation alters nociceptive response in a gender‐dependent manner in rats

“…Therefore, our results indicate that maternal deprivation may alter supraspinally and spinal pain pathways, principally after a short‐time exposure to the stressor (at P21).Corroborating these data, previous study by our group, using the TFL, showed that male rats at P14 presented an increased response to repeated morphine administration without developing tolerance in relation to P8, which can be related to maturation process of opioid pathway. These same animals, at P80, showed greater morphine analgesia and the classic tolerance opioid (Rozisky et al, 2008). In addition, Weaver and Diorio (2007) showed that neonatal stress leads to a persistent reduction in pain sensitivity in female adult rats (P120), possible due to the greater μ‐opioid receptor binding capacity.…”

Morphine exposure during early life alters thermal and mechanical thresholds in rats

“…However, at P80, the rats experienced greater morphine analgesia and a classic tolerance effect. In addition, the animals that received morphine from P8 until P14 displayed a longer duration of morphine analgesia at the same age (P80) (Rozisky et al, 2008). Another study by our group showed that animals subjected to repeated morphine exposure during early life (5 μg/day for 7 days s.c. from P8 until P14) showed a hypernociceptive behavior in adult life (Rozisky et al, 2011).…”

Morphine exposure and maternal deprivation during the early postnatal period alter neuromotor development and nerve growth factor levels

“…Studies have demonstrated that changing morphine sensitivity in the postnatal period may be a part of a general reorganization in the structure and function of primary afferent synapses, neurotransmitter/receptor expression and function, and excitatory and inhibitory modulation from higher brain centers (Fitzgerald and Howard, 2003; Pattinson and Fitzgerald, 2004). A previous study by our research group showed that newborn rats might be more sensitive to low doses of morphine (Rozisky et al, 2008) because an extensive remodeling of opioid receptor expression takes place in the first 3 postnatal weeks (Beland and Fitzgerald, 2001). The density of binding decreases in the first 3 postnatal weeks, with peak binding at P7, which then falls to adult levels by P21 (Beland and Fitzgerald, 2001).…”