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

Background: Morphine is an opioid analgesic used to relieve moderate-to-severe pain, including pain in neonates at the intensive care unit. In our previous study, we showed that repeated morphine exposure during early life could trigger long-lasting implications on the developing nervous system, such as long-term neurochemical and behavioral alterations in adult rats.

Aims: The aim of our study was to determine the short-, intermediate-, and long-term effects of repeated morphine administration during early life on the thermal and mechanical thresholds and on the central levels (cerebral cortex and brainstem) of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and cytokines (interleukin-6 [IL-6] and IL-10).

Methods: Male Wistar rats were administered morphine (5μg/day, s.c.) or saline for 7days from postnatal day 8 (P8) until P14. The nociceptive effect was assessed by evaluating the thermal response using the hot plate test (HPT) and the mechanical response by Von Frey (VFT) and Randall-Selitto (RST) tests at P16, P30, and P60. BDNF, NGF, IL-6, and IL-10 levels were measured in the cerebral cortex and brainstem.

Results: In HPT, no difference in latency was observed at P16; however, at P30 and P60, the morphine-treated group exhibited a less increase in the nociceptive threshold compared to the saline group. VFT and RST demonstrated an interaction between group and age, where the morphine group showed a less pronounced increase in latency with age, which is indicative of allodynia. In the cerebral cortex, an association between BDNF and NGF levels and age was observed, where neurotrophin level increased with age in the saline group, and decreased with age in the morphine group. In addition, IL-10 levels decreased with age in both groups; however, there was no significant difference in IL-6 levels. In the brainstem, BDNF, NGF, IL-6, and IL-10 levels increased with age.

Discussion: Repeated morphine exposure during neonatal life triggered alterations in the nociceptive behavior, including thermal hyperalgesia and mechanical allodynia, as well as decreased levels of BDNF and NGF in the cerebral cortex. Our study highlights the importance of extensive comprehension of the pharmacological interventions during CNS maturation.