Pain: a Tale of 3 Systems
The hypothalamic-pituitary-adrenal axis: at the center of the neuroendocrine-immune link for pain.
As efforts to improve chronic pain treatment continue, some experts propose that the focus should shift toward the multifaceted etiology of pain itself.
Pharmaceutical treatments for chronic pain are based on a view of pain as arising solely from neuronal activation, and this narrow view has resulted in treatments that are largely ineffective, according to the authors of a review published in the Journal of Translational Medicine.1
Though “there is a classical view that pain is due to altered neuronal responses only, we now have a better understanding that this is not the case,” said Ihssane Zouikr, PhD, a postdoctoral fellow at the RIKEN Brain Science Institute in Wako, Japan.
“To understand pain, we need to understand the interaction between the immune, endocrine and nervous systems and how alteration in one system will lead to alteration in the whole ‘mutisystem' network,” he told Clinical Pain Advisor.
In the recent review, Dr Zouikr and colleagues from the University of Newcastle in Australia examined evidence regarding the complex origins of pain. In addition, they called for an expanded approach to pain assessment that integrates perinatal programming and early life events, which can affect how individuals experience pain and respond to treatment.
Early Adverse Events & the HPA Axis
The hypothalamic-pituitary-adrenal (HPA) axis is a primary mediator of the stress response, and pain is one type of stressful experience. HPA axis activation by corticotropin-releasing hormone and vasopressin leads to an increase in circulating adrenocorticotropic hormone (ACTH) that results in cortisol production (or, in rodents, corticosterone production).
“The HPA axis goes through a period of significant change and development during the perinatal period, and exposure to adverse events during this period is known to produce long-term alterations in neuroendocrine function and behavior,” wrote the authors.
In utero exposure to stress, for instance, has been associated with impaired endocrine function in humans later in life, and in utero exposure to chronic maternal distress has been linked with increased responsivity of the HPA axis in subsequent years.2
Results of animal research studies similarly show that stress exposure during the perinatal period can lead to long-term alterations of the HPA axis.3
Studies are increasingly finding that children who are exposed to adverse events are more likely to demonstrate impaired functioning of the HPA axis and exaggerated stress responses in adulthood. This could be due in part to reduced hippocampal volume, as has been observed in adults who experienced poor maternal care or sexual abuse as children.4,5
Nociceptive Plasticity in the Neonatal Period
In the neonatal period, further evidence shows a significant degree of plasticity of the nociceptive system. For example, spinal dorsal horn cells in deep laminae are not responsive to input from C fibers until 7 or 8 days postnatally, and rat pups do not exhibit C-fiber-evoked reflexes in response to mustard oil until 10 or 11 days postnatally.6
In addition, the “activation of C fibres is unable to evoke spike activity in the spinal cord before the second postnatal week (and) Aδ fibres are completely unmyelinated until the pups reach 2–3 weeks,” according to the review.
This window of plasticity renders the infant brain particularly vulnerable to early injury that could result in altered pain responses later in life. This has been demonstrated in research involving children who were born preterm, as such infants are routinely exposed to painful procedures in the course of their critical care. In one study, infants who had undergone heel lances already showed hyperalgesia during venipuncture, when compared to unexposed infants.7
The Neuroendocrine-Immune Link
There are numerous possible mechanisms underlying the link between hyperalgesia and early adverse events, including neuroimmune responses.
In recent years, the role of the immune system in pain has become well-established. “Pain is by nature inflammatory, so there is activation of immune cells at the peripheral level and in the central nervous system,” explained Dr Zouikr.
“When these immune cells are activated, they release pro-inflammatory cytokines–such as interleukin1-beta (IL-1-β), tumor necrosis factor-alpha, and others–that contribute to exaggerated pain responses.”
Interleukin IL-1 was found to directly activate the HPA axis and promote the release of glucocorticoids.8,9 Other studies revealed that IL-1β injections stimulated release of corticosterone and ACTH, and immunoneutralization of IL-1β blocked its stimulatory effect on ACTH.10,11
Clinical Summary & Applicability
Considering the sum of the evidence, the authors encourage clinician education about the multisystem interaction involved in pain, including the stress response system as one component, in order to improve patient care and treatment.
“Instead of targeting only the neuronal component of pain, we need to target the inflammatory processes or the endocrine system,” for example, and future research should further elucidate the role of the various systems in pain modulation, said Dr Zouikr.
“But also clinicians need to consider the early life history of their patients when treating chronic pain, because aberrant early life experience might contribute to their altered pain responses,” he noted.
- Zouikr I, Bartholomeusz MD, Hodgson DM. Early life programming of pain: focus on neuroimmune to endocrine communication. J Transl Med. 2016; 14:123.
- O'Connor TG, Ben-Shlomo Y, Heron J, Golding J, Adams D, Glover V. Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry. 2005; 58(3):211-7.
- Shanks N, Larocque S, Meaney MJ. Neonatal endotoxin exposure alters the development of the hypothalamic-pituitary-adrenal axis: early illness and later responsivity to stress. J Neurosci.1995; 15(1 Pt 1):376-84.
- Buss C, Lord C, Wadiwalla M, et al. Maternal care modulates the relationship between prenatal risk and hippocampal volume in women but not in men. J Neurosci. 2007; 27:2592–2595.
- Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A, Teicher MH. Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci. 2008; 20:292–301.
- Fitzgerald M. The post-natal development of cutaneous afferent fibre input and receptive field organization in the rat dorsal horn. J Physiol. 1985; 364:1–18.
- Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002; 288:857–861.
- Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986; 233:652–654.
- Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science. 1987; 238:522–524.
- Uehara A, Gottschall PE, Dahl RR, Arimura A. Stimulation of ACTH release by human interleukin-1 beta, but not by interleukin-1 alpha, in conscious, freely-moving rats. Biochem Biophys Res Commun. 1987; 146:1286–1290.
- Berkenbosch F, van Oers J, del Rey A, Tilders F, Besedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science. 1987; 238:524–526.