The long-term impact of early life pain on adult responses to anxiety and stress: Historical perspectives and empirical evidence

Abstract

Approximately 1 in 6 infants are born prematurely each year. Typically, these infants spend 25 days in the Neonatal Intensive Care Unit (NICU) where they experience 10-18 painful and inflammatory procedures each day. Remarkably, pre-emptive analgesics and/or anesthesia are administered less than 25% of the time. Unalleviated pain during the perinatal period is associated with permanent decreases in pain sensitivity, blunted cortisol responses and high rates of neuropsychiatric disorders. To date, the mechanism(s) by which these long-term changes in stress and pain behavior occur, and whether such alterations can be prevented by appropriate analgesia at the time of insult, remains unclear. Work in our lab using a rodent model of early life pain suggests that inflammatory pain experienced on the day of birth blunts adult responses to stress- and pain-provoking stimuli, and dysregulates the hypothalamic pituitary adrenal (HPA) axis in part through a permanent upregulation in central endogenous opioid tone. This review focuses on the long-term impact of neonatal inflammatory pain on adult anxiety- and stress-related responses, and underlying neuroanatomical changes in the context of endogenous pain control and the HPA axis. These two systems are in a state of exaggerated developmental plasticity early in postnatal life, and work in concert to respond to noxious or aversive stimuli. We present empirical evidence from animal and clinical studies, and discuss historical perspectives underlying the lack of analgesia/anesthetic use for early life pain in the modern NICU.

Keywords: Amygdala; Corticosterone; Corticotrophin releasing factor receptors; Endogenous opioids; Endorphin; Enkephalin; Glucocorticoid receptor; Hypothalamic pituitary adrenal axis; Morphine; Periaqueductal gray.

Figure 1. The lasting impact of a single neonatal injury on HPA activity and circuits responsive to noxious stimuli

A. Preterm infants experience numerous painful, inflammatory procedures in the Neonatal Intensive Care Unit often in the absence of pain therapy. To model a single painful experience on the day of birth, rat pups receive an injection of the inflammatory agent carrageenan (CGN; 1%) into the intraplantar surface of the right hind paw. B. Inflammatory pain increases afferent nociceptive drive to supraspinal brain regions responsive to noxious stimuli (e.g. septum, thalamus, hypothalamus, amygdala and periaqueductal gray (PAG); diagram and brain plates adapted from (Hunt and Mantyh, 2001) and (Paxinos and Watson, 2005), respectively). Met-enkephalin (ENK), β-endorphin (β-ENDO) and corticosterone (CORT) are released to dampen pain perception and stress associated with inflammation. ENK and plasma CORT remain elevated at the end of the first postnatal week, suggesting permanent changes in the endogenous opioid and stress systems. C. In neonatally injured adults (D) CORT levels return to baseline more rapidly following acute stress stimulation of the hypothalamic pituitary adrenal (HPA) axis. In parallel, glucocorticoid receptor (GR) mRNA and protein are increased in the paraventricular nucleus of the hypothalamus but decreased in the dorsal and ventral hippocampus, suggesting support for accelerated negative feedback. E. Anatomical changes in corticotrophin releasing factor receptor (CRFR) 1 and 2, and ENK are observed in circuits that process anxiety-, stress-, and pain-provoking stimuli, contribute to stimulation of the HPA axis and homeostasis. CRFR1 binding is significantly decreased in the amygdala and ventrolateral (vl) PAG. CRFR2 binding was increased in the amygdala and lateral septum (LS). ENK mRNA and protein expression are significantly increased in the vlPAG, amygdala and LS.

Figure 2. The lasting impact of a single neonatal injury on anxiety and stress responding

A. In response to acute stressors (forced swim), neonatally injured adults take significantly longer to initiate floating. By contrast, adults injured early in life float rapidly after exposure to 7 days of mild chronic variable stress (mCVS). B. Hypo-sensitivity to acute stress-provoking stimuli and hyper-sensitivity to sequential, unpredictable stress are rescued if male and female rats are given morphine for early life pain, suggesting that 1) injury-induced behavioral and hormonal vulnerability are preventable, 2) neonatal pain is necessary for the long-term changes in stress responding. (Abbreviations: corticosterone, CORT; area under the curve, AUC).