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. Author manuscript; available in PMC: 2017 Feb 1.
Published in final edited form as: Curr Opin Behav Sci. 2016 Feb;7:61–68. doi: 10.1016/j.cobeha.2015.11.015

Exposure to Early Life Pain: Long Term Consequences and Contributing Mechanisms

Nicole C Victoria 1,1, Anne Z Murphy 1,*
PMCID: PMC4979223  NIHMSID: NIHMS745104  PMID: 27525299

Abstract

From an evolutionary perspective, adaptations of an organism to its early environment are essential for survival. The occurrence of early life perturbation, coincident with increased developmental plasticity, provides a unique opportunity for such adaptations to become programmed and persist throughout life. However, adaptations that are beneficial to maintaining homeostasis in one's early environment may result in extreme response strategies that confer vulnerability or dysfunction later in life. This review summarizes recent findings in human and animal studies demonstrating that early life pain results in a hypo-/hyper-sensitive phenotype in response to acute and persistent pain and stress later in life. Changes in cognition and immune function in response to early life pain have also been observed. Recent data on the neural mechanisms underlying these long-term changes are discussed, as well as potential strategies to minimize the impact of early life pain.

Graphical abstract

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Overview

Each year, up to 18% of infants worldwide and 11.4% of infants in the United States are born prior to 37 gestational weeks (GW) and are considered preterm [1,2]. Advances in medical technology now allow for ~80% of infants born by 26 GW to survive ex utero [3]. Preterm infants typically spend more than one month in the Neonatal Intensive Care Unit (NICU) [4], where they undergo a median of 16 invasive procedures each day, including repeated heel lance, endotracheal intubation, surgery, and respiratory and gastric suctioning [5]. Despite the recognition that these interventions produce pain, inflammation, and stress, specific analgesia or anesthesia is only used for 2-21% of NICU procedures [5]. Historically, infants and children were considered incapable of engaging in higher-level sensory processing, including nociception [6]. However, overwhelming evidence over the last 30 years demonstrates that premature and term infants are able to perceive noxious stimuli. Indeed, cortical responses to noxious peripheral stimulation (heel prick) have been reported in infants as young as 25 GW [7]. Fear of negative long-term consequences associated with opiate exposure has also contributed to under-management of pain for NICU patients. Recent studies, however, report that former preterm infants who received morphine for pain management had improved executive function relative to those that received placebo [8,9]. With the appreciation that neonates do indeed feel pain, research devoted toward evidence-based strategies for pain management, using both pharmacologic and non-pharmacologic approaches are required.

The long-term impact of early life pain in humans

Initially, preterm infants display elevated behavioral, hormonal and autonomic responses to invasive NICU procedures [10]. However, the experience of repeated, unalleviated pain at this early developmental time point results in rapid adaptations, as evidenced by reductions in autonomic and hormonal responses to pain and stress that persist into adolescence and adulthood [10]. Changes in brain maturation and cognitive processing have also been reported. Here, we will review the most recent preclinical and clinical evidence related to the long-term impact of early life pain on sensory perception, endocrine function, as well as behavioral, emotional and cognitive outcomes [11,12].

Sensory perception

Imaging studies report higher metabolic activity and functional connectivity in the thalamus and sensory cortices for preterm infants (24-32 GW) relative to full term peers [13], suggesting enhanced integration of sensory information. Initially, EEG responses and facial reactivity of preterm infants are high in response to procedural pain, however, these measures decrease as the number of skin breaking procedures increases [11,14]. By 3 months of age, these infants show attenuated behavioral responses to acute noxious stimuli (e.g. reduced duration of crying and facial reactivity), but heightened withdrawal responses to pain from consecutive immunizations [15]. Former NICU adolescents and teenagers are similarly less sensitive to brief thermal pain, but exhibit enhanced sensitivity to prolonged painful heat or cold stimulation [16-19]. These data suggest that the experience of early life pain increases general pain thresholds to acute stimuli (hypo-sensitive), but exaggerates responses to severe and/or persistent noxious stimuli (hyper-sensitive) later in life.

Endocrine responses to stress and affective state

Early life pain also results in long-term changes in stress reactivity. In response to procedural pain, heart rate and cortisol levels of preterm infants are initially high, but like pain behavior, become blunted as the number of skin breaking procedures increase [11,14]. At 3 months of age, former preterm infants show reductions in both autonomic arousal and cortisol reactivity in response to immunization pain as compared with term peers [15]. By age 7, greater neonatal procedural pain predicts lower levels of acute and diurnal cortisol among preterm infants [20,21], and lower cumulative cortisol relative to term peers [20,21]. As physiological changes in response to stress are associated with disorders of anxiety, depression, obessive compulsion, panic and post-traumatic stress [22,23], such findings suggest that early life pain reprograms the hypothalamic pituitary adrenal (HPA) axis, putting preterm infants at higher risk for developing maladaptive responses to anxiety- and stress-provoking stimuli. Indeed, affective dysfunction in former preterm infants is associated with blunted cortisol reactivity by 7 years of age [21], suggesting that the hypo-/hyper-sensitive profile to acute and severe perturbations extends beyond pain sensitivity and is a more generalized long-term adaptation associated with early life pain.

Not surprisingly, early life pain directly predicts later-life affective state. Increases in pain and distress to heel lance in the NICU are associated with higher levels of negative affect for former preterm toddlers [24-26], and a recent meta-analysis shows former preterm infants between 11-20 years of age are 45% more likely to develop clinically significant issues of anxiety [27]. Consistent with this, higher rates of anxiety, depression, attention deficit hyperactivity disorder and reduced behavioral flexibility are self- or parent-reported in former preterm infants versus term peers up to 20 yrs of age [19,28]. Together, these data suggest that the experience of early life pain increases the risk for the development of affective disorders later in life.

Brain development and cognitive functioning

Long-term changes in brain development and cognitive functioning have also been linked to early life pain. For example, in infants born at 24-32 GW the number of skin breaking procedures experienced is highly correlated with decreased white and gray matter maturation at 40 GW [29], and altered neurodevelopmental outcomes at 1.5 years [30]. Moreover, thinning over ~30% of cortical regions, especially in frontal and parietal areas, and reduced cognition and visual-motor integration is observed at 7-8 years of age in association with early life pain [11,31]. During perceptual reasoning, reductions in spontaneous cortical gamma-to-alpha ratio oscillations, task-dependent network synchrony, and functional interaction between brain regions are also observed in former preterm infants at 7-8 years [32,33]. Despite these findings, children exposed to early life pain demonstrate higher perceptual sensitivity in low-stimulus intensity environments relative to term peers [34], consistent with hypo-/hyper-sensitive profiles observed in response to pain and stress.

Alterations in gamma-alpha oscillations and network synchrony correlate significantly with psychiatric and neurological disorders (e.g. schizophrenia, autism, Alzheimer's disease) [35,36], suggesting that early life pain may be a significant risk factor for later-life neuropathology. Indeed, at age 10, early life pain is associated with increased volume of the amygdala [37], a key region implicated in stress, anxiety, and pain that becomes dysregulated following bouts of anxiety, depression, and PTSD. These data, together, suggest that brain development and functioning of broad neural circuits underlying executive, cognitive and emotional processing are likely reprogrammed by early life pain to have large scale and potentially life-long influences on neurobehavioral and neuropsychiatric outcomes.

Evidence from animal models parallels observations in humans

Despite differences in the type of tissue injury used in animal models of early life pain (e.g. 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. By contrast, adult exposure to chronic unpredictable stress significantly enhances depression-like behavior and elevates corticosterone release relative to neonatally uninjured controls [43,44]. In addition, neonatal pain impairs spatial learning and memory in middle-aged rats, and this cognitive impairment can be precipitated early in adulthood by exposure to 7 days of chronic variable stress [45]. These findings, together, parallel the hypo-/hyper-sensitive profile observed in humans as a result of unresolved early life pain. 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].

Mechanisms contributing to the long-term consequences of early life injury

Injury-induced changes in descending modulation

The endogenous pain modulatory circuit, consisting of the periaqueductal gray (PAG) and its descending projections to the rostral ventromedial medulla (RVM) and spinal cord dorsal horn, changes both anatomically and physiologically in response to early life injury [47]. These changes are both immediate and permanent. Within 24 hrs of P0 hindpaw inflammation, midbrain ß-endorphin and enkephalin protein levels increase significantly, and remain elevated one week post-injury [48]. Elevated levels of endogenous opioids are a necessary strategy to rapidly combat the pain and maintain homeostasis, and makes sense in terms of survival, as this is likely the only mechanism available at this developmental time point to dampen the pain. However, ß-endorphin and enkephalin mRNA and protein levels remain significantly elevated within the PAG into adulthood [43], indicating that early life pain permanently reprograms opioidergic circuits that are critical for pain management. Enhanced descending inhibition from the RVM [49] and increased excitability within the spinal cord dorsal horn [50-52] have also been reported in adult animals that experienced early life pain (see review:[53]). 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.

Injury-induced changes in neuronal excitability

While early life injury results in a hypo-sensitive phenotype to acute noxious stimuli, the opposite response, hyper-algesia, is observed following the experience of a more severe and persistent insult [41,42]. This hypo/hyper-sensitive profile parallels what is reported clinically. Studies both in vitro and in vivo report that injury in the first postnatal week results in potentiated glutamatergic signaling in the neonatal superficial dorsal horn [41,55]. This change in intrinsic spinal cord signaling is thought to prime developing pathways and enhance future responses to subsequent tissue damage [41,55]. Lamina I projection neurons also show increased excitatory postsynaptic current (EPSC) amplitudes in neonatally injured adults, as well as increased afferent input from low threshold myelinated Aδ (nociceptive) fibers, and decreased GABAA and glycine receptor contributions to inhibitory postsynaptic currents (IPSCs) [52]. Altered excitation and inhibition of adult lamina II neurons has also been reported [51]. Together, this enhanced spinal network activity favors facilitated nociception, and is a likely mechanism through which hyperalgesia can override the basal hypo-sensitivity observed in humans and animal models as a result of early life pain. Interestingly, these changes in spinal signaling were prevented by pre-emptive regional nerve block or morphine, again suggesting increased nociceptive drive as the primary mechanism [41,55].

Mechanisms contributing to the long-term changes in response to stress

Long term, albeit permanent changes in the neural circuits underlying stress are also observed following unresolved pain in neonates. Paralleling clinical studies, inflammatory pain on P0 blunts adult behavioral and hormonal responses to acute anxiety- and stress-provoking stimuli in rats, while adult exposure to chronic unpredictable stress significantly enhances depression-like behavior and facilitates corticosterone release relative to uninjured controls [43,44]. Like pain, adult hypo-sensitivity to acute stress-provoking stimuli is reversed by systemic administration of μ-or δ-opioid receptor antagonists, suggesting that changes in the endogenous opioid system underlie the observed hypo-sensitivity to acute stress. As well, enkephalin mRNA and protein are significantly upregulated in the adult amygdala and septum, two key regions that mediate stress and anxiety [43]. Endogenous opioids have been shown to modulate the perception of stress, and stressors of several different modalities elicit their release. Indeed, many stressors have been shown to induce an analgesic response that is cross-tolerant with morphine and is antagonized by naloxone (see [56] for review). Of note, and paralleling what is reported for the pain system, morphine analgesia for early life pain rescues adult behavioral responses to stress [44]. The observed blunting of the HPA axis, while adaptive in response to early life pain, is highly maladaptive later in life as failure to recognize salient stimuli in the environment as potentially dangerous increases vulnerability to life-threatening situations. Indeed, an attenuated stress response, coupled with a decrease in pain sensitivity, likely contributes to the increased risk taking behavior observed in former NICU infants [57].

Additional mechanisms contributing to HPA dysregulation

To meet the energetic demands of stressful stimuli, including pain, tissue damage or inflammation, glucocorticoids are released from the HPA axis, and eventually bind to GR in the hypothalamus and hippocampus as part of the negative feedback loop to terminate further glucocorticoid release. Prolonged pain and inflammation in the early neonatal period results in sustained HPA axis activation and disruption of the stress hypo-responsive period (SHRP; P2-14), which relies on low levels of postnatal glucocorticoids to promote critical developmental processes (e.g. neurogenesis, axon growth, synaptogenesis, myelination) (see: [39]). Corticosterone levels are elevated 24 hours and 7 days following P0 inflammation of the hindpaw [48], and likely contribute to the increase in cortical thinning and elevated apoptosis observed in numerous brain regions over the first postnatal week in rats [58]. Interestingly, neonatally injured adults show increased GR mRNA and protein levels in the hypothalamus that likely facilitate negative feedback, and may compensate for decreased levels of GR in the hippocampus [59]. Like humans, adult corticosterone levels are blunted in response to acute stress, and return to baseline more rapidly than controls [48]. However, repeated HPA activation by 7 days of chronic variable stress in adulthood elevates and prolongs reactivity, paralleling clinical data showing early life pain induces a hypo-/hyper-sensitive HPA axis. Given that corticosterone and GR regulate hippocampal-dependent cognition, injury-induced decreases in hippocampal GR likely contribute to the observed deficits in spatial learning and memory of adult neonatally injured rats and may contribute to the cognitive challenges reported in former NICU infants [45].

In addition to changes in GR, early life pain in rodents significantly decreases corticotrophin releasing factor (CRF) receptor 1 (CRFR1; associated with stress-promotion) [60] in the amygdala and vlPAG, while increasing amygdalar and septal CRFR2 (associated with stress-reduction) [59]. Notably, these regional changes overlap anatomically with those observed for enkephalin, suggesting that early life pain modifies a common neural circuit that, in turn, affects later-life response to stress-, anxiety- and pain-provoking stimuli [39,56].

Potential contributions from immune factors

Early life pain and stress may act as a proinflammatory stimulus that induces long-term immune cell activation [20]. In particular, glucocorticoids have been shown to regulate expression of immune-related genes, and conversely, dysregulation of immune/inflammatory responses may play a central role in mediating the early programming effects of the HPA axis [61]. Recently, common genetic variants in the promoter region of the NFKBIA gene was shown to modulate the link between NICU-associated pain and stress with HPA axis programming [20]. NFKBIA encodes IκBα, a critical negative regulator of the transcription factor NF-κB, which in turn regulates the expression of the majority of proinflammatory cytokines, chemokines and leukocyte adhesion molecules, as well as pro-survival and anti-apoptosis genes. Dysregulation of NF-κB is a known consequence of early life stress [62,63], and likely contributes to the increased incidence of chronic pain syndromes [64] and anxiety disorders [20] observed in former NICU patients. Interestingly, mice subjected to nerve injury in the first postnatal week have increased spinal levels of the anti-inflammatory cytokines IL-4 and IL-10 [65], but as adults show increased spinal levels of the pro-inflammatory cytokine TNF that is associated with thermal and mechanical hyperalgesia [65]. This hypo-/hyper-sensitive immune profile is consistent with other adaptations observed as a result of early life pain, and clearly warrants additional investigation. Although a direct link between endogenous opioids and immune cell function has not been demonstrated in vivo, opioid receptors are expressed in the majority of immune cells, including T cells, macrophages and microglia, and morphine has been shown to suppress NF-κB expression, decrease astrocyte proliferation, and desensitize chemokine receptors [66]. This suggests that the observed increase in endogenous opioids in response to early life pain not only impacts subsequent responses to pain and stress, but immune function as well.

Remediation of consequences associated with early life pain

The long-term consequences of early life pain can be mitigated by treatment with appropriate analgesics. For example, former preterm infants that received continuous low-dose morphine (10 μg/kg/h) for pain management in the NICU show improved executive functioning, reduced externalization and no adverse effects on pain sensitivity at age 8-9 years versus infants that received placebo [8,67]. Consistent with this, administration of morphine or local nerve block at the time of neonatal injury completely reverses the hypo-/hyper-sensitive phenotype observed in rodents in response to acute/chronic pain-, anxiety-, and stress-provoking stimuli [41,44,45,54,55,58]. Non-pharmacologic therapies may also attenuate later-life consequences, as kangaroo care, massage therapy, skin-to-skin contact, breast feeding/non-nutritive suckling or oral sweeteners (alone or in combination) reduce stress hormone levels and pain responses to acute procedural pain [9,68]. Last, parental factors can also attenuate the long-term consequences of early life pain, as increases in parental emotional sensitivity and education and lower parental stress are associated with decreased internalization and increased cognitive performance for toddlers that experienced a high number of skin breaking procedures in the NICU [25,69].

Summary and Conclusions

Human and animal studies report that exposure to unalleviated pain early in life has immediate and long-lasting consequences for sensory perception, stress responsiveness, and emotional health that are characterized by a hypo-/hyper-sensitivity in response to acute versus chronic and/or severe stimuli. Changes in brain development and cognition, as well as immune function, have also been reported. The mechanisms by which these long-term changes occur are not entirely clear, but accumulating evidence indicates that changes in endogenous opioids, as well as the stress associated hormones or peptides (glucocorticoids, CRF) and their receptors, contribute to the observed changes. As early life pain significantly increases the risk for developing disorders of anxiety, depression and potentially PTSD, the use of specific and appropriate analgesic/anesthetic regimes for human infants is imperative.

Figure 1.

Figure 1

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The experience of early life pain produces immediate and long-term changes in sensory perception, hormone and peptide release, and behavioral responses that are similar between humans and animal models. In immediate response to unalleviated pain (top), spinal excitability increases, enhancing the transmission of nociceptive signals to the brain, evidenced as crying and facial reactivity in the neonate. In turn, the endogenous opioids enkephalin and endorphin are released within the periaqueductal gray (PAG) of the descending modulatory system to dampen pain perception. Anti-inflammatory cytokines increase in the spinal cord as well. Concurrently, the stress system is activated, elevating CORT (cortisol in humans and corticosterone in rodents) over a prolonged period to meet the energetic demands associated with the pain and inflammation of injury. Later in life, a duality of hypo-/hyper-sensitivity (middle, bottom: left column) is observed. In response to acute or generalized pain-, anxiety-, and stress-provoking stimuli, or challenge of executive function, hypo-sensitivity is observed. In contrast, hyper-sensitive responses are observed following exposure to chronic or severe perturbations. Evidence from both clinical and preclinical studies have identified mechanisms (middle, bottom: right column) that underlie or contribute to the maintenance of these later-life states. Increased enkephalin is observed in the PAG, amygdala and lateral septum, areas responsive to noxious, aversive stimuli. CRFR1 is decreased in the amygdala and PAG, while CRFR2 is increased in the amygdala, and lateral septum. The regional overlap between changes in enkephalin and CRFRs, suggests a common circuit responsive to early life pain. (Right column) Most, (perhaps all) long-term consequences associated with early life pain can be prevented by analgesic treatment with either morphine or nerve blocking agents. Oral sweeteners, breast feeding/non-nutritive suckling may also be effective. High levels of parental care, in and outside of the NICU, as well as parental education, are essential factors that significantly mitigate the consequences of early life pain. Additional abbreviations: corticotrophin releasing factor receptor (CRFR1, CRFR2); glucocorticoid receptor (GR); paraventricular nucleus of the hypothalamus (PVN); dorsal and ventral hippocampus (dHPC, vHPC).

Highlights.

Early life pain induces long-term changes in response to pain, anxiety, and stress.

Injury-induced changes in pain, anxiety and stress are due to increased opioid tone.

Analgesic administration at the time of injury mitigates the negative consequences.

Former NICU infants similarly display a hypo-/hyper-sensitive response profile.

Footnotes

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References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest

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