Surgical Injury in the Neonatal Rat Alters the Adult Pattern of Descending Modulation from the Rostroventral Medulla

Abstract

Background-Neonatal pain and injury can alter long-term sensory thresholds. Descending rostroventral medulla (RVM) pathways can inhibit or facilitate spinal nociceptive processing in adulthood. As these pathways undergo significant postnatal maturation, we evaluated long-term effects of neonatal surgical injury on RVM descending modulation.

Exposure to early life pain: long term consequences and contributing mechanisms

“…This blunted adult pain sensitivity is mediated by endogenous opioids, as systemic or intra-PAG administration of μ- or δ-opioid receptor antagonists attenuates the hypoalgesia [54]. Administration of morphine at the time of injury reverses the adult hypoalgesia [54], supporting the hypothesis that unalleviated early life pain permanently alters the postnatal development of the endogenous pain modulatory circuit [41,42]. While a decrease in pain sensitivity may initially seem attractive, it is highly maladaptive as failure to respond to tissue-damaging stimuli increases the risk of severe injury.…”

“…acute or repeated injury, inflammatory agents, surgical incision; see reviews [38,39]), findings support clinical data showing long-term changes in response to pain and stress, affective behavior and cognition. For example, adult rats exposed to surgery or inflammatory pain in the first postnatal week (developmentally comparable to a 24-36 GW infant [40]) exhibit significant hypo-sensitivity to acute thermal or mechanical noxious stimuli, but hyper-sensitivity to chronic, more intense nociceptive stimulation [41,42]. Similarly, inflammatory pain on postnatal day (P)0 significantly blunts adult behavioral sensitivity and corticosterone release in response to acute anxiety- and stress-provoking stimuli.…”

“…They also indicate that different types of early life cutaneous damage result in similar consequences, indicating a common mechanism. Importantly, in all cases, pre-emptive morphine or local nerve block rescued adult behavioral and hormonal responses such that neonatally injured rats were indistinguishable from controls later in life [41,44-46]. …”

Translational studies identify long-term impact of prior neonatal pain experience

“…3A) Importantly, peri-operative sciatic nerve blockade at the time of neonatal incision (30 minutes pre-incision and 3x2hrly percutaneous injections of 0.5% levobupivacaine) normalizes sensory thresholds in adulthood (Fig. 3B) and prevented the effects of neonatal injury on adult reflex withdrawal threshold and normalized the pattern of descending modulation [209]. The common finding of raised sensory thresholds in preterm clinical cohorts and following hindpaw inflammation/incision strengthens the validation of these early life injury models in the rodent, and also identifies a mechanistic link between neonatal tissue injury and long-term alterations in sensory processing.…”

“…As also seen following neonatal hindpaw inflammation, [162] the generalized distribution suggests a central mechanism and raised thresholds emerge only after 3-4 weeks of age. [209] During this same developmental period, descending inhibitory modulation also matures, [77; 78; 104; 178] but this may be influenced by prior injury. In young adult animals, electrical stimulation in the rostroventral medulla (RVM) produced the typical intensity-dependent bimodal pattern of inhibition or facilitation of hindlimb reflex response.…”