Opioid analgesia and the somatosensory memory of neonatal surgical injury in the adult rat

Abstract

BackgroundNociceptive input during early development can produce somatosensory memory that influences future pain response. Hind-paw incision during the 1st postnatal week in the rat enhances re-incision hyperalgesia in adulthood. We now evaluate its modulation by neonatal analgesia.MethodsNeonatal rats [Postnatal Day 3 (P3)] received saline, intrathecal morphine 0.1 mg kg−1 (IT), subcutaneous morphine 1 mg kg−1 (SC), or sciatic levobupivacaine block (LA) before and after plantar hind-paw incision (three×2 hourly injections). Six weeks later, behavioural thresholds and electromyography (EMG) measures of re-incision hyperalgesia were compared with an age-matched adult-only incision (IN) group. Morphine effects on spontaneous (conditioned place preference) and evoked (EMG sensitivity) pain after adult incision were compared with prior neonatal incision and saline or morphine groups. The acute neonatal effects of incision and analgesia on behavioural hyperalgesia at P3 were also evaluated.ResultsAdult re-incision hyperalgesia was not prevented by neonatal peri-incision morphine (saline, IT, and SC groups > IN; P<0.05–0.01). Neonatal sciatic block, but not morphine, prevented the enhanced re-incision reflex sensitivity in adulthood (LA < saline and morphine groups, P<0.01; LA vs IN, not significant). Morphine efficacy in adulthood was altered after morphine alone in the neonatal period, but not when administered with neonatal incision. Morphine prevented the acute incision-induced hyperalgesia in neonatal rats, but only sciatic block had a preventive analgesic effect at 24 h.ConclusionsLong-term effects after neonatal injury highlight the need for preventive strategies. Despite effective analgesia at the time of neonatal incision, morphine as a sole analgesic did not alter the somatosensory memory of early-life surgical injury.

Early life nociception is influenced by peripheral growth hormone signaling

“…5b) after P35 incision compared to WT controls. We then confirmed previous reports (Walker et al, 2009) (Moriarty et al, 2018) that an early life muscle incision (P7) in WT control mice followed by a P35 incision resulted in a longer lasting mechanical hypersensitivity compared to mice with P35 incision alone. Interestingly, if treatment with GH was given at the time of the early life injury (P7), prolonged hypersensitivity was not detected after the second incision (Fig.…”

“…These "priming" effects of neonatal injury have been linked to alterations in the central nervous system (Walker et al, 2016) (Baccei, 2016) (Brewer and Baccei, 2019). However, evidence suggests that there is also a peripheral component that has been less explored (Moriarty et al, 2018). We have shown that the pattern of primary afferent sensitization and injury-related receptor/channel expression in the DRGs after neonatal peripheral injury is unique to that observed in adult nociceptors (Jankowski et al, 2014) (Liu et al, 2017) (Ye and Woodbury, 2010) (Koerber et al, 2010) (Koerber and Woodbury, 2002).…”

“…Beyond acute sensitization, it has become clear that early life injury induces neuronal and immunological alterations that, when re-activated by an insult later in life, results in enhanced pain-like outcomes (Ren et al, 2004) (Boissé et al, 2005) (Walker et al, 2009) (Schwaller et al, 2015) (Moriarty et al, 2019) (Zhong et al, 2018). While a number of analyses of the central nervous and immune system have confirmed that this "priming" effect requires central processing, it is clear that primary afferent input is also necessary (Moriarty et al, 2019) (Beggs et al, 2012) (Walker et al, 2016) as opioid treatment could not alter neonatal priming responses but sciatic nerve block could (Moriarty et al, 2018). As our current (Fig.…”

“…As such, neonates are particularly vulnerable to sensory impairment during developmental injury (Lim and Godambe, 2017). Recent work in animals (Ren et al, 2004) (Walker et al, 2009) and humans (Hermann et al, 2006) (Walker et al, 2018) (Moriarty et al, 2018) (Walker, 2019) indicates that early life injury enhances pain-related responses later in life. These "priming" effects of neonatal injury have been linked to alterations in the central nervous system (Walker et al, 2016) (Baccei, 2016) (Brewer and Baccei, 2019).…”

Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery

“… 70 , 71 Importantly, prevention by peri-incision local anaesthetic suggests activity-dependent mechanisms that can be modulated by clinically-relevant analgesic interventions. 3 , 72 Although UK paediatric anaesthetists in 1995 reported regular use of opioids and local anaesthetic techniques for neonates requiring surgery, 73 specific data for preterm neonates and this cohort are not available. Additional clinical studies are required to compare the ability of different systemic or regional analgesic techniques to modulate the long-term impact of neonatal surgery.…”