Dual effects of brain sparing opioid in newborn rats: Analgesia and hyperalgesia

Gong Kerui,Luc Jasmin

doi:10.1016/j.ynpai.2018.01.001

Gong Kerui, Luc Jasmin

Open Access

https://doi.org/10.1016/j.ynpai.2018.01.001

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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.

Highlights

Unrelieved pain in the term and preterm neonate initiates maladaptive plasticity that can persist later in life (Schwaller and Fitzgerald, 2014; Walker et al, 2016)
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 of dorsal root ganglia (DRGs) and spinal nociceptive neurons
Since there is a greater expression of mu-opioid receptors (MORs) in primary sensory neurons during the first 2 post-natal weeks (Beland and Fitzgerald, 2001; Nandi et al, 2004), we postulated that newborns would be ideal candidates for loperamide induced antinociception

Summary

Introduction

Unrelieved pain in the term and preterm neonate initiates maladaptive plasticity that can persist later in life (Schwaller and Fitzgerald, 2014; Walker et al, 2016) Opioids can prevent this plasticity while providing analgesia. Given that opioids are effective analgesics for acute pain, a possible strategy is to use brain sparing (peripherally acting) opioids in the newborn. To explore this approach we chose the brain sparing MOR agonist loperamide (Guan et al, 2008; Kumar et al, 2012; Nozaki-Taguchi and Yaksh, 1999). Given that brain penetrant opioids can produce pro-nociceptive effects (Roeckel et al, 2017), we tested the effect of daily loperamide on the nociceptive threshold, the peripheral neuronal activity using patch clamp recordings, and the CNS activity using Fos immunochemistry

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Conclusion