Targeting p38 Mitogen-activated Protein Kinase to Reduce the Impact of Neonatal Microglial Priming on Incision-induced Hyperalgesia in the Adult Rat

Schwaller, Fred; Beggs, Simon; Walker, Suellen M.

doi:10.1097/aln.0000000000000659

Cited by 36 publications

(57 citation statements)

References 79 publications

(122 reference statements)

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“…This is evident by the increase in toll-like receptor 4 (78) associated with post-circumcision wound healing, which is also observed in post-surgical tactile hypersensitivity in males and dependent on testosterone (79). Following peripheral nerve injury, the purinergic receptors in the spinal cord microglial cells release BDNF (79) and mitogen-activated protein kinase p38 (80) that contribute to neuropathic pain and tactile hypersensitivity. Due to their testosterone dependency, they are seen only in males (79).…”

Section: Introductionmentioning

confidence: 99%

“…Neonatal surgery that traumatizes peripheral nerves with associated tactile hypersensitivity followed by a subsequent surgery later in development can increase spinal cord microglia signaling and elicit persistent hyperalgesia (80). It can also produce post-surgical hyperalgesia that subsequently alters postnatal development of the rostral rostroventral medulla (RVM), which controls the excitability of spinal neurons by spinally projecting neurons from the nucleus paragigantocellularis lateralis (PGCL) and the nucleus raphe magnus.…”

Section: Introductionmentioning

confidence: 99%

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A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Elhaik

2016

Front. Neurol.

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Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A “Wear and Tear” Hypothesis to Explain Sudden Infant Death Syndrome

Elhaik

2016

Front. Neurol.

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“…[12] The degree and distribution of neuronal pERK expression 15 minutes after adult incision was also not significantly different in animals with and without prior incision. [176] While these findings suggest a centrally-mediated mechanism that is independent of peripheral tissue injury, the extent to which the 'memory' of early injury is determined by alterations in microglial phenotype or is secondary to enhanced synaptic signaling (see Section 4.4) is difficult to differentiate, and both are likely to play a role. Evaluating the ability of microglial inhibitors at the time of neonatal incision to prevent enhanced hyperalgesia following adult incision would further support a role for microglia, but potential sex differences in glial signaling [124; 183] also need to be considered.…”

Section: Impact Of Prior Incision On Spinal Microglia Response In Adumentioning

confidence: 95%

“…3A). [176] Whereas primary afferent activity at the time of neonatal injury is required to initiate longterm alterations (as evidenced by preventive effects of neonatal perioperative sciatic block) (Fig. 3B), it is not the sole driver of the enhanced injury response in adulthood.…”

Section: Impact Of Prior Incision On Spinal Microglia Response In Adumentioning

confidence: 99%