Dual effects of brain sparing opioid in newborn rats: Analgesia and hyperalgesia
2018
Abstract Effective pain management in neonates without the unwanted central nervous system (CNS) side effects remains an unmet need. To circumvent these central effects we tested the peripherally acting (brain sparing) opioid agonist loperamide in neonate rats. Our results show that: 1) loperamide (1 mg/kg, s.c.) does not affect the thermal withdrawal latency in the normal hind paw while producing antinociception in all pups with an inflamed hind paw. 2) A dose of loperamide 5 times higher resulted in only 6.9 ng/mL of loperamide in the cerebrospinal fluid (CSF), confirming that loperamide minimally crosses the blood–brain barrier (BBB). 3) Unexpectedly, sustained administration of loperamide for 5 days resulted in a hyperalgesic behavior, as well as increased excitability (sensitization) of dorsal root ganglia (DRGs) and spinal nociceptive neurons. This indicates that opioid induced hyperalgesia (OIH) can be induced through the peripheral nervous system. Unless prevented, OIH could in itself be a limiting factor in the use of brain sparing opioids in the neonate.
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