The Neurobiology of Pain: Development and Sex
Abstract and Keywords
The influence of development and sex on pain perception has long been recognized but only recently has it become clear that this is due to specific differences in underlying pain neurobiology. This chapter summarizes the evidence for mechanistic differences in male and female pain biology and for functional changes in pain pathways through infancy, adolescence, and adulthood. It describes how both developmental age and sex determine peripheral nociception, spinal and brainstem processing, brain networks, and neuroimmune pathways in pain. Finally, the chapter discusses emerging evidence for interactions between sex and development and the importance of sex in the short- and long-term effects of early life pain.
Pain and Development
Our knowledge of the neurobiology of nociception and pain has made great advances in recent years, particularly in recognizing the importance of factors influencing individual sensitivity to pain. Two such factors stand out: the developmental biology of pain and the biology of sex differences in pain. Research has revealed the importance of both developmental plasticity and sex in determining nociceptive function from the cellular level to the individual pain experience. This chapter highlights key knowledge and questions in the two fields and discusses their role in determining pain sensitivity, pain behavior, and susceptibility to chronic pain.
Early Nociceptive and Pain Behavior
Newborn mammals show robust nociceptive reflex behavior following a noxious mechanical stimulus (Baccei & Fitzgerald, 2013; Fitzgerald, 2005). Such behavior is essential if the infant is to attract help and preserve its life. Perhaps because of this, infant reflexes are stronger than the equivalent ones in adults: withdrawal of the limb from a noxious mechanical stimulus applied to the foot is exaggerated in amplitude and duration (Ekholm, 1967; Fitzgerald, 2005). With this excitability comes a lack of specificity: neonatal withdrawal reflexes are not nociceptive specific and can be elicited by (p. 390) nonpainful stimuli (such as light touch). The very low mechanical sensory thresholds in newborn rat pups are also observed in preterm infants and increase steadily with age (Cornelissen et al., 2013). In addition, nociceptive reflex receptive fields are large and disorganized with the poor spatial organization and high incidence of misdirected nociceptive reflex movements in young mammals (Waldenström, Thelin, Thimansson, Levinsson, & Schouenborg, 2003). Human infants also show a notable radiation of nociceptive reflexes to involve extensor as well as flexor muscles and both contralateral and ipsilateral limbs. Repeated tactile and noxious skin stimulation results in sensitization of the reflexes and generalized movements of all limbs, which becomes less pronounced after 29–35 weeks’ gestational age in the human and the first postnatal week in the rat (Fitzgerald, 2005).
Behavioral responses to noxious heat stimulation are also exaggerated in the newborn rat (Falcon, Guendellman, Stolberg, Frenk, & Urca, 1996), while the response to some chemical irritants is less robust (Fitzgerald & Gibson, 1984), probably due to the absence of TRPA1 (Transient receptor potential cation channel, subfamily A, member 1) channel expression in immature nociceptors (Hjerling-Leffler, Alqatari, Ernfors, & Koltzenburg, 2007).
Maturation of Nociceptors and Dorsal Horn Nociceptive Circuits
The sensitivity and lack of spatial focus in newborn nociceptive reflexes is a direct result of the immaturity of the spinal circuitry that underlies them. Thus, understanding the maturation of nociceptive afferent signaling, the formation of central synaptic connections, and the developmental organization of dorsal horn nociceptive circuitry is key to understanding newborn pain behavior.
Maturation of Nociceptors
Nociceptive primary afferent neurons in the dorsal root ganglia (DRG) arise from a late wave of embryonic neurogenesis, well after the majority of low-threshold touch afferents are born. Initially all newborn nociceptor neurons express the nerve growth factor (NGF) receptor TrkA (tropomyosin receptor kinase A), but over perinatal and postnatal development, they segregate into the proto-oncogene tyrosine-protein kinase receptor Ret-expressing (nonpeptidergic) and TrkA-expressing (peptidergic) subtypes and begin to express a variety of sensory receptors and ion channels under the control of transcription factors and growth factors (Lallemend & Ernfors, 2012).
Polymodal nociceptors, responding to noxious cutaneous mechanical, thermal, and selected chemical stimulation, can be functionally identified as soon as their axons innervate target skin (Fitzgerald, 2005). However, the proportion of functional subtypes changes with age: C fiber polymodal (CPM) neurons increase markedly relative to C fiber mechanically sensitive, thermally insensitive (CM) neurons after the (p. 391) first postnatal week (Jankowski et al., 2014) as transduction mechanisms mature (Hjerling-Leffler et al., 2007).
Developing Dorsal Horn Nociceptive Circuits
The central processes of nociceptive C fibers grow into the dorsal horn just before birth, but the subsequent maturation of their synaptic connections is slow. C-fiber–evoked mEPSC frequency and action potential firing in superficial and deep dorsal horn neurons is very weak at birth and increases significantly in the second postnatal week (Baccei, Fitzgerald, & Fitzgerald, 2003). Mechanical pinch elicits c-Fos expression in dorsal horn cells from birth, the protein kinase R (PKR)-like endoplasmic reticulum kinase, pERK activation in response to noxious heating and capsaicin application is minimal until the second postnatal week (Fitzgerald, 2005; Walker, Meredith-Middleton, Lickiss, Moss, & Fitzgerald, 2007). The weak synaptic input from C fibers means that A fibers, both low- and high-threshold mechanoreceptor (LTMR and HTMR), afferents, are dominant in the immature dorsal horn, compounded by the fact that A-fiber afferent terminals spread more widely into the superficial laminae of the dorsal horn in early life and are only pruned back to their adult position in laminae III–V over the following weeks (Beggs, Torsney, Drew, & Fitzgerald, 2002; Granmo, Petersson, & Schouenborg, 2008), most likely by the actions of phagocytic microglia (Xu, Moulding, Gibbs, & Beggs, 2019; Q. Li & Barres, 2018). Thus, while newborn dorsal horn cells respond to both innocuous and noxious mechanical cutaneous inputs, the proportion of the wide dynamic range (responding to both) neurons markedly increases postnatally, suggesting increased sensory convergence with age (Baccei & Fitzgerald, 2013). The dominance of A-fiber synaptic inputs into the dorsal horn likely underlies the low cutaneous sensory thresholds and prolonged afterdischarges that characterize immature dorsal horn cells of action potentials. Furthermore their receptive fields are relatively larger than those of mature dorsal horn cells, such that each neuron is activated by a larger area of the body surface than in adults, gradually decreasing over the first two postnatal weeks (Ririe, Bremner, & Fitzgerald, 2008; Torsney & Fitzgerald, 2002).
A further critical feature of immature dorsal horn is the absence of functional, targeted glycinergic inhibition. In adults, Aβ fibers synapse directly onto glycinergic interneurons, and glycine receptor antagonists enhance tactile behavioral sensitivity and increase A-fiber excitation of dorsal horn neurons producing a pattern of activity analogous to that seen in the healthy developing neonate (Koch & Fitzgerald, 2013; Sherman & Loomis, 1996). However, there is little glycinergic activity in newborn lamina II: miniature inhibitory postsynaptic currents are low frequency and mediated by gamma-aminobutyric acid A (GABAA) receptors, and the glycine transporter GLYT2 in presynaptic glycinergic terminals matures slowly, reaching adult termination patterns in laminae IIi and III by P14. This important delay in the maturation of fast inhibitory control contributes to the enhanced sensitivity and reduced spatial discrimination to both tactile and noxious mechanical stimulation (Baccei & Fitzgerald, 2004; Koch, Tochiki, Hirschberg, & Fitzgerald, 2012).
(p. 392) Response of Immature Nociceptive Afferents and Dorsal Horn Neurons to Tissue Damage or Injury
Tissue injury during development may be accompanied by inflammation and nerve injury. How this affects the responses of immature nociceptive afferents and dorsal horn neurons is discussed next.
Tissue injury or inflammation in newborn mammals evokes significant behavioral pain hypersensitivity from birth. Repeated heel lances in newborn infants (Fitzgerald, Millard, & MacIntosh, 1988) and mechanical and thermal hyperalgesia, as well as spontaneous pain behaviors, have been widely observed in neonatal rats following the administration of inflammatory agents or surgical incision(Baccei & Fitzgerald, 2013). This hyperalgesia arises from peripheral and central sensitization, both of which occur at birth but undergo postnatal maturation.
Nociceptor sensitization to repeated noxious stimulation or inflammatory mediators is a feature of even the most immature nociceptors (Koltzenburg & Lewin, 1997). NGF is upregulated to a greater extent following skin injury in young compared to adult animals and induces a profound and long-lasting sensitization of Aδ-nociceptive afferents to mechanical (but not thermal) stimuli (Lewin, Ritter, & Mendell, 1993). Central sensitization of dorsal horn circuits can also be demonstrated from a very early age, which explains the inflammatory hyperalgesia behavior described previously. Hind paw inflammation increases A-fiber–evoked sensitization, spontaneous activity, and the suprathreshold response magnitude of dorsal horn cells from postnatal day 3, but unlike the adult, receptive field size is not increased, perhaps because it is already relatively large in area (Torsney & Fitzgerald, 2002).
Importantly, selective activation of neonatal C-fiber nociceptors with mustard oil or capsaicin induced primary, but not secondary, mechanical hyperalgesia. Secondary hyperalgesia matures more slowly, illustrating the importance of mature central circuitry in this spreading of sensitivity away from the site of injury (Walker et al., 2007). While extracellular signal-regulated kinase (ERK) protein is present in the newborn dorsal horn, capsaicin application produces minimal ERK activation, which is consistent with the absence of behavioral secondary hyperalgesia described previously, further evidence that primary and secondary hyperalgesia are differentially modulated during development (Walker et al., 2007).
Pain arising from peripheral nerve injury (PNI), however, is highly dependent on the age at which the damage occurs. Nerve injury performed in animals less than 3–4 weeks of age did not cause any pain behavior (Howard, Walker, Michael Mota, & Fitzgerald, 2005); this is consistent with observations in very young patients who do not display any neuropathic pain following traumatic nerve injury (Fitzgerald & McKelvey, 2016). However, (p. 393) in rodent models that underwent nerve injury before 10 days of age, pain hypersensitivity emerged later in life, when the animal reached adolescence (Vega-Avelaira, McKelvey, Hathway, & Fitzgerald, 2012). This delayed, late-onset neuropathic sensitivity is caused by the changing profile of the dorsal horn immune response to nerve injury (McKelvey, Berta, Old, Ji, & Fitzgerald, 2015). In contrast to adult nerve injury, which triggers a pro-inflammatory immune response in the spinal dorsal horn, infant nerve injury triggered an anti-inflammatory immune response characterized by significant increases in interleukin (IL) 4 and IL-10. This immediate anti-inflammatory response could also be evoked by direct C-fiber nerve stimulation in infant, but not adult, mice (McKelvey et al., 2015). Blockade of the anti-inflammatory activity with intrathecal anti–IL-10 unmasked neuropathic pain behavior in infant nerve-injured mice, showing that pain hypersensitivity in young mice was actively suppressed by a dominant anti-inflammatory neuroimmune response. As infant nerve-injured mice reach adolescence, the dorsal horn immune profile switches from an anti-inflammatory to a pro-inflammatory response characterized by significant increases in tumor necrosis factor (TNF) and bone-derived neurotrophic factor (BDNF), and this is accompanied by late-onset neuropathic pain behavior and increased dorsal horn cell sensitivity to cutaneous mechanical and cold stimuli (McKelvey et al., 2015). Thus, neuropathic pain following early life nerve injury is not absent but is suppressed by neuroimmune activity and can still emerge at adolescence, when the neuroimmune profile changes (Fitzgerald & McKelvey, 2016).
The Role of Sensory Experience in Developing Nociceptive Circuits
Sensory experience plays a role in developing nociceptive circuits. This is demonstrated by their dependence upon a normal balance of sensory activity in early life and the priming effects of tissue injury during development.
The postnatal maturation of nociceptive circuits in the dorsal horn is an activity-dependent process. Thus normal, background sensory stimulation, which drives dorsal horn activity via glutamate/NMDA (N-methyl-d-aspartate) receptors in the postnatal period, is required for the normal developmental processes to occur. The pruning of A-fiber terminals, the reduction of receptive field size, the focusing of nociceptive reflexes, and the reduction of cutaneous mechanical sensitivity were all delayed or inhibited by prolonged blockade of NMDA-dependent neuronal activity in the dorsal horn (Beggs et al., 2002; Granmo et al., 2008; Waldenström et al., 2003). The absence of glycinergic inhibitory signaling and the exuberant A-fiber input to the newborn dorsal horn and resulting low-threshold motor activity is likely to facilitate activity-dependent synaptic strengthening. Intriguingly, this period of excitability ends with the maturation of targeted (p. 394) glycinergic inhibition in these circuits, which is in turn driven by the increasing maturation of nociceptive C-fiber connections in the dorsal horn (Koch et al., 2012). Any repeated or long-lasting intervention that alters the level of neural activity in the newborn dorsal horn therefore has the potential to alter the normal development of spinal cord pain circuitry.
Priming by Early Life Injury
Immature dorsal horn circuits are highly vulnerable to excessive noxious stimulation or inflammatory injury at birth, and evidence is increasing that spinal sensory circuits underlying touch and pain processing can be shaped by early life pain experience. There is considerable evidence that skin incision injury in early life can “prime” pain pathways, leading to greater pain behavior after repeat injury in adults (Beggs, Currie, Salter, Fitzgerald, & Walker, 2012; Moriarty, Harrington, Beggs, & Walker, 2018; Schwaller, Beggs, & Walker, 2015); it also occurs following early life inflammation (Schwaller & Fitzgerald, 2014; Walker, 2013). There is increasing clinical evidence to support the importance of this priming (Walker, Melbourne, et al., 2018; Walker, O’Reilly, Beckmann, Marlow, & EPICure@19Study Group, 2018), which is proposed to be a potential factor in individual vulnerability to chronic pain (Denk, McMahon, & Tracey, 2014).
The mechanisms underlying early life pain priming are not known but are likely to involve a combination of developmental neural and immune plasticity. It requires nerve activity generated at the time of injury (Walker, Tochiki, & Fitzgerald, 2009) but is not affected by opioid analgesia at that time (Moriarty et al., 2018). Nociceptors are highly vulnerable to skin injury and local inflammation in early life. Skin wounding in young animals triggered lasting cutaneous sensory nerve sprouting, leading to pain and sensitivity, a process that is driven by upregulation of neurotrophin 3 (NT-3) (Beggs, Alvares, et al., 2012). Furthermore, the discovery that the classic pro-inflammatory pathway, TNF-α/TNFR1 (tumor necrosis factor receptor 1), was required for normal development of nociceptor sensitivity through antagonism of NGF-TrkA signaling (Wheeler et al., 2014) suggests that if this pathways is unbalanced by early life tissue damage, nociceptor sensitivity may be permanently altered. This is supported by the finding that cutaneous inflammation in the first week of life specifically altered the mechanical and heat responsiveness and heat thresholds in Aδ nociceptors (Jankowski et al., 2014) through local regulation of growth hormone (X. Liu et al., 2017).
Neonatal surgical injury also enhanced nociceptive excitatory synaptic strength (J. Li & Baccei, 2011) and widened the timing window during which correlated presynaptic and postsynaptic activity can evoke long-term potentiation (LTP) in adult lamina I projection neurons (J. Li & Baccei, 2016). In addition, repeated neonatal noxious heel prick or innocuous hind paw stimulation enhanced dorsal horn spike activity to cutaneous dynamic tactile (brush), pinch, and punctate stimulation in adult rats and significantly enhanced the injury sensitivity of adult wide-dynamic range neurons to both noxious and dynamic tactile stimulation (van den Hoogen et al., 2018).
The developing neuroimmune system plays a key role in this priming process. The enhanced hyperalgesia that follows early life injury is accompanied by increased (p. 395) microglial activity in the dorsal horn and is blocked by local p38 inhibitors (Beggs, Currie, et al., 2012; Schwaller et al., 2015). The dorsal horn microglial response to injury in neonates differs from that in adults (Moss et al., 2007; Vega-Avelaira, Géranton, & Fitzgerald, 2009), and microglia may have an important phagocytic role in neonatal dorsal horn that, if altered by early life injury, could lead to lifelong changes in neural function. Spinal microglial blockers administered at the time of neonatal injury can block the priming of adult pain sensitivity, but in male mice (Moriarty et al., 2019) (see Sex Differences in Spinal Pain Processing).
Developing Cortical Pain Networks
To generate pain, nociceptive information must be transmitted via ascending projection pathways to the thalamus and cortex, and maturation of cortical pain networks is essential to pain development (Verriotis, Chang, Fitzgerald, & Fabrizi, 2016). Spinothalamic projection neurons develop in midgestation and by birth have attained adult numbers and terminal distribution in the ventrobasal complex of the thalamus (Davidson, Truong, & Giesler, 2010). However, functional mapping of nociceptive inputs to the thalamus and other supraspinal centers suggests slow postnatal maturation of these synaptic connections after the first postnatal week (Barr, 2011). The peripheral and spinal cord sensory pathways and the central thalamocortical and corticothalamic pathways start their development separately and only interact at later stages. Thus, the early stages of thalamocortical development take place autonomously, with the information from the periphery “plugging into” these immature circuits before beginning to transmit spontaneous and later somatosensory information (Molnár, 2019). Thalamocortical projections form their first functional synaptic connections in the subplate region at E18 to E19, extending into layers IV, V, and VI of the developing somatosensory cortex in a topographically precise manner at birth. The refinement of topographical projections from the thalamus to the cortex arises through an activity-dependent process in which thalamic axons compete for cortical targets. Subplate neurons are crucially involved in the generation of early network activity (Tolner, Sheikh, Yukin, Kaila, & Kanold, 2012), and if this activity is altered during a critical period in early development, normal connectivity is disrupted. Synaptic connections are strengthened during development by correlated pre- and postsynaptic activity and NMDA receptor–dependent LTP (H. Li & Crair, 2011).
Sensory discriminative aspects of pain begin in the somatosensory cortex, and functional development of nociceptive input to this area of cortex occurs slowly over the postnatal period in rodents. During this period, the sensorimotor cortex expresses transient patterns of correlated neuronal activity, including delta waves, gamma- and spindle-burst oscillations largely driven by the thalamus and triggered, in a topographic manner, by sensory feedback resulting from spontaneous movements (Khazipov & Milh, 2018). Responses to peripheral sensory stimulation can be recorded a few days after birth, but these are poorly tuned to stimulus modality and location. Nonspecific (p. 396) overlapping receptive fields become more specific and topographically organized in the developmental period postnatal days 5–20 (Seelke, Dooley, & Krubitzer, 2012). Under light anesthesia, intracortical extracellular field potentials can be evoked by hind paw C-fiber electrical stimulation at P7; this activity also increases in amplitude and complexity over the next few weeks (Chang, Fabrizi, Olhede, & Fitzgerald, 2016). The response to noxious stimulation has a larger theta frequency component (4–8 Hz) in younger rat S1 cortex, suggesting a maturational change in nociceptive networks over this period (Devonshire, Greenspon, & Hathway, 2015).
Direct age comparisons in cortical activity can be confounded by the developmental regulation of anesthetic action and the remarkable resistance of nociceptive evoked potentials to even high levels of volatile anesthetics (Chang, Walker, & Fitzgerald, 2015). Therefore, the introduction of continuous telemetric electrocorticogram (ECoG) recording from the primary somatosensory cortex (S1) of awake active rat pups to map functional pain processing in the developing brain over the first weeks of life has been an important step in this field (Chang et al., 2016). In awake pups, baseline S1 ECoG energy increases steadily with age, with a distinctive beta component replaced by a distinctive theta component in the third postnatal week. Event-related potentials are evoked by brief noxious hind paw skin stimulation from P7, confirming the presence of functional nociceptive spinothalamic inputs in S1. Hind paw incision, which causes hypersensitivity at all ages, did not increase S1 ECoG energy until the third week, when it caused a significant increase in gamma (20- to 50-Hz) energy accompanied by a longer lasting increase in theta (4- to 8-Hz) energy. The specific postnatal functional stages in the maturation of S1 cortical nociception suggests that somatosensory cortical coding of ongoing pain in awake rat pups undergoes critical development between 2 and 4 weeks of age (Chang et al., 2016).
Developing Cortical Pain Networks: Emotional and Motivational Aspects
Many ascending nociceptive pathways are directed toward the amygdala, medial prefrontal cortex, which are proposed to subserve the emotional or affective aspects of pain. Functional mapping of these connections in young rodents showed that these pathways matured later than direct spinothalamic pathways (Verriotis et al., 2016). Thus, there is no nociceptive spinal input to either the parabrachial (PB) nucleus or the ventrolateral periaqueductal gray (vlPAG) before postnatal day 12 (Schwaller, Kwok, & Fitzgerald, 2016) when the somatosensory cortex can be clearly activated by nociceptive input (Chang et al., 2015). This suggests slower maturation of pathways responsible for signaling emotional, relative to nociceptive or sensory, components of pain.
Mapping brain activation using manganese-enhanced magnetic resonance imaging (MEMRI) suggested that both limbic and sensory paths are functional by 12 postnatal days (Sperry et al., 2017). The neural circuitry of the medial prefrontal cortex (mPFC), (p. 397) an area of the brain that is key to assessing the threat of sensory stimuli and generating defensive responses, progressively develops more capacities as the animal matures. When rats are exposed to a threatening stimulus at 14 days old, the mPFC is neither active nor responsive, but becomes responsive in processing aversive sensory stimulation at 26 days, but only finally regulates freezing in adolescence at P38 to P42 days (Chan et al., 2011).
The amygdala is the central component of a functional brain system regulating fear and emotional behaviors. Distinct behaviors related to amygdala activation emerge at different time points during postnatal development and continue to mature during late postnatal development (Tallot, Doyère, & Sullivan, 2016). Infant rats do not show freezing behavior until about P10, the age at which they begin to make brief excursions outside the nest, coincident with emergence of activity within the amygdala. The fear startle response only appears after weaning. The role of the parent may be critical: findings from the rodent and human literature showed that the presence/absence of the parent was critical to the development of amygdala activation and fear learning (Tottenham & Gabard-Durnam, 2017).
More complex functions in the cortex require linked activity in several areas carried out by large-scale neuronal networks integrating several cortical areas. Little is known about the functional development of these networks in relation to pain and the maturational processes by which distant networks become functionally connected (Verriotis et al., 2016). Recordings across the whole cortical surface together with intracortical electrodes revealed that sensory-evoked cortical responses matured continuously throughout the first 3 weeks, with the strongest developmental changes occurring in a very short time around the end of week 2 (Quairiaux, Mégevand, Kiss, & Michel, 2011).
Maturation of Top-Down Control of Nociception
An important feature of cortical function is that it can modify spinal cord nociceptive circuits through activation of descending pathways. Brainstem centers, the rostroventral medulla (RVM) and periaqueductal gray (PAG), driven by the amygdala and other brain regions can exert both inhibitory and facilitatory effects on spinal excitability and pain sensitivity in the adult (Heinricher, Tavares, Leith, & Lumb, 2009). The postnatal maturation of this descending control is slow and goes through a series of different functional states: in the first 10 days of life, the RVM receives no ascending input from spinal circuits and so functions independently of sensory input, exerting tonic descending excitation on dorsal horn cells (Schwaller et al., 2016), likely generated by spontaneous brainstem activity. Later in postnatal life, ascending nociceptive inputs reach the RVM, so forming a functional spinal-bulbo-spinal feedback loop. However, the dominance of excitatory descending control over spinal nociceptive processing continues for 4 postnatal weeks. Thus, top-down control over spinal nociceptive circuits switches from predominantly excitatory to predominantly inhibitory so that descending inhibition becomes gradually more powerful until adulthood (Hathway, Koch, Low, & Fitzgerald, 2009).
(p. 398) The mechanism underlying this change in top-down control is likely to lie in the maturation of the cortex and of RVM and PAG circuitry. The maturation of brainstem opioidergic signaling is an important factor: blockade of tonic opioidergic activity in the brain over a critical period from 3 to 4 weeks prevents the normal development of descending RVM inhibitory control of spinal nociceptive reflexes, while enhancing brain opioidergic activity with chronic morphine accelerates this development (Hathway, Vega-Avelaira, & Fitzgerald, 2012). These changes in supraspinal control over dorsal horn neuronal activity and nociceptive reflexes over a critical periadolescent developmental period impacts the ability of the brain to control the effects of painful stimulation and are likely to be of key importance in setting future pain sensitivity in adulthood.
Plasticity, Pain, and the Developing Brain
How and when the brain develops to encode noxious stimuli, create the experience of pain, and drive the appropriate emotional and motivational response is an area of important current research. This information has clear clinical implications for devising analgesic strategies in hospitalized children, tailored to the developmental stage of the individual. Evidence suggests that sensory and nociceptive systems and their associated perceptive abilities are established during specific developmental time windows or “critical periods.” Deprivation of normal external inputs or disruption of physiological neuronal activity at these stages causes long-lasting sensory impairment. While it is difficult to define a critical period for the nociceptive system, both clinical studies and animal models have shown that early exposure to noxious procedures may cause long-term alterations of pain perception, descending pain control, and associated brain structures (Duerden et al., 2018; Walker et al., 2018). The mechanisms underlying this long-term brain plasticity are as yet incompletely understood.
Pain and Sex
The second part of this chapter discusses sex and gender differences in clinical pain and pain neurobiology. Phenotypic and epidemiological sex differences in clinical pain have been well characterized. The literature on mechanistic differences in pain is less extensive, but sex differences in the neurobiology of pain are being increasingly uncovered, including differences between females and males in peripheral nociceptive mechanisms, spinal pain processing, and descending regulatory control.
Studies on sex, gender, and pain have been growing in number over the past decade, reflecting increased awareness of the importance of sex and gender differences in chronic pain and in biological phenomena in general. However, there remains a substantial gap in inclusion of female subjects in preclinical as well as clinical pain research. (p. 399) In preclinical studies, a major contributor to this sex bias appears to be fear surrounding additional variability imposed by the estrous cycle (Mogil, 2012; Mogil & Chanda, 2005). This fear is unwarranted as analyses of large data sets showed that male and female rodents had similar variability in pain behaviors (Mogil & Chanda, 2005). If anything, males trended toward slightly higher variability than females (Mogil & Chanda, 2005). The sex bias in preclinical pain research has led to a dearth of knowledge on the fundamental mechanisms underlying chronic pain in females, seemingly because many investigators have not considered the possibility that the mechanisms that may underlie chronic pain in females may differ from those in males. Recent publications, however, have shed light on profound sex differences in pain biology.
Sex and Gender in Clinical Pain
Here we discuss why there are sex and gender differences in chronic pain prevalence and why girls and women are more at risk.
Sex and Gender Differences in Chronic Pain Prevalence
It is widely known that women are more likely to suffer from chronic pain than men, although chronic pain is a considerable public health concern in both sexes (Berkley, 1997; Fillingim, King, Ribeiro-Dasilva, Rahim-Williams, & Riley, 2009; Mogil, 2012). This sex difference in pain prevalence exists across almost all forms of chronic pain, including neuropathic pain, back pain, headaches, migraine, fibromyalgia, and osteoarthritis. For example, 35.0% of female participants in a nationwide survey of the French general public reported generalized chronic pain, defined in the survey as daily pain that persisted longer than 3 months (Bouhassira, Lantéri-Minet, Attal, Laurent, & Touboul, 2008). Self-report of chronic pain in males was significantly lower at 28.2%. Analysis of the subpopulation of survey respondents with neuropathic pain found that the sex difference in prevalence rate was maintained. Chronic pain with neuropathic characteristics occurred in 8.0% and 5.7% of females and males, respectively (Bouhassira et al., 2008). Although the exact rates tended to differ across studies, the sex difference in chronic pain prevalence was consistent across studies.
Childhood pain—such as persistent headaches, recurrent abdominal pain, and musculoskeletal pain—is also more prevalent in girls than in boys (King et al., 2011). The sex difference in pain prevalence persists throughout adolescence, despite an overall increase in the rate of most pain conditions with age. Psychosocial factors such as anxiety, poor self-esteem, low socioeconomic status, and depression were associated with persistent pain among youth of both sexes (King et al., 2011). However, it remains unclear whether any of these variables contribute to the sex difference in pain prevalence.
Chronic pain is not universally more predominant in females than in males. Several chronic pain conditions are more common—or exclusive—to males, such as ankylosing spondylitis, gout, and chronic prostatitis, of course (Mogil, 2012).
(p. 400) Why Are Girls and Women More at Risk?
As discussed, the epidemiological literature overwhelmingly shows that across the life span chronic pain conditions are significantly more prevalent in females than in males. A major unresolved question is why women and girls have greater susceptibility to chronic or persistent pain. Three major contributors have been proposed in the literature.
One possibility is that epidemiological studies may not provide an accurate representation of chronic pain prevalence. This could occur because women may more readily seek help for their pain from healthcare providers than men, a phenomenon that has been documented in the general health literature (Mogil, 2012). Further, there may be a gender difference in reporting bias, in that males are less likely to report their pain when surveyed. Combined, underdiagnosing and underreporting of chronic pain could contribute to an inaccurate estimation of this condition among males, thus inflating the sex difference in prevalence rates (Mogil, 2012).
A second possibility is that females may be more sensitive or less tolerant to pain overall. A heightened experience of pain, regardless of the underlying mechanisms, could result in more females fulfilling the diagnostic criteria for chronic pain (Mogil, 2012). Indeed, an analysis of a large database of electronic medical records from 11,000 patients found that clinical pain scores were significantly higher in women than in men with the same disease diagnosis (Ruau, Liu, Clark, Angst, & Butte, 2012). Of relevance to chronic pain, women with acute inflammatory conditions such as sinusitis reported higher pain scores than males. The higher pain scores reported by women were documented in many different types of disease and were most robust in musculoskeletal, circulatory, digestive, and respiratory disorders (Ruau et al., 2012). These findings suggest that females may experience increased pain intensity relative to males under similar pathophysiological conditions.
Further, meta-analysis of laboratory nociceptive sensitivity has revealed that females are consistently more sensitive to experimenter-applied noxious stimuli (Mogil, 2012). The difference in degree of experimentally evoked pain between men and women appears to be relatively minor; however, its existence has been observed in a large majority of laboratory studies. This sex difference is consistent across stimulus modalities (e.g., cold pain, heat pain, pressure pain, and muscle pain) as well as across dependent measure (e.g., tolerance vs. threshold, intensity vs. unpleasantness) (Mogil, 2012). Whether the sex differences in acute nociceptive pain evoked in controlled laboratory settings relate to clinical differences in chronic pain in females compared with males remains to be determined.
A third possibility is that females are more at risk of developing chronic pain. The sex difference in prevalence rates could reflect that females are more susceptible to chronic pain. This enhanced susceptibility could be due to a combination of biological, psychological, or social factors. Sex differences in pain biology have been demonstrated (Loyd, Morgan, & Murphy, 2007, 2008; Loyd & Murphy, 2006; Mogil, 2012; Sorge et al., 2011, 2015; Taves et al., 2015) and are discussed in more detail further in the chapter. (p. 401) Female-specific pain mechanisms could be more vulnerable to pathological insults, facilitating the development of chronic pain.
The sex difference in chronic pain prevalence likely derives from an interaction of factors, such as those discussed above. Given that women and girls represent a population with a greater risk of developing chronic pain, understanding the mechanisms underlying sex and gender differences is critical for developing effective diagnostic and therapeutic approaches, which may need to be tuned to sex and gender.
Sex Differences in Peripheral Nociceptive Mechanisms
A potential contributor to the greater sensitivity of females to acute nociceptive pain and heightened susceptibility to chronic pain in females is that primary afferent nociceptor activity is greater in females than males when exposed to identical stimuli. This possibility has been investigated indirectly through human studies where acute nociceptive stimuli were applied peripherally. A caveat is that differences in pain reports or behavioral changes may reflect differences in nociceptive processing in the central nervous system (CNS) rather than, or in addition to, differences in peripheral nociceptors. Observations such as that epidermal nerve fiber density is greater in women than men hints that the greater sensitivity to acute nociceptive stimuli in the female may have a peripheral basis. But knowledge of whether nociceptor discharge activity evoked by acute noxious stimuli in women is different from that in men remains a gap in understanding.
To attempt to relate sex differences in nociceptive-evoked pain to primary afferent discharge, a common stimulus (injecting glutamate into the masseter muscle) was used in healthy humans and rats (Cairns, Hu, Arendt-Nielsen, Sessle, & Svensson, 2001). The magnitude of glutamate-evoked pain in women was greater than that in men, and glutamate elicited higher muscle afferent discharge activity in female than in male rats. Thus, amplified pain perception in women after glutamate administration might be a result of potentiated peripheral pain signaling (Cairns et al., 2001).
In contrast, the mechanical threshold C-fiber nociceptors innervating muscle was found to be higher in female rats than in male rats (Hendrich et al., 2012). Other characteristics of the nociceptors did not significantly differ in vivo or in ex vivo recordings from DRG neurons in acute culture. Thus, it was concluded that lowered nociceptive threshold in females may be due to sex differences in CNS mechanism, and that these differences would need to be sufficiently big to overcome the opposing difference in mechanical threshold in the primary afferents.
Recently, using a model of ischemia/reperfusion (I/R), mechanically sensitive muscle afferents in female rats were found to have greater mechanical and heat responsiveness than did those in male rats (Ross, Queme, Lamb, Green, & Jankowski, 2018). These afferents in females also showed alterations in heat responsiveness, which can be attributed to sex differences in gene expression within the affected DRGs. Regardless, both sexes showed similar increases in I/R-induced pain-like behaviors.
(p. 402) Sex differences are known in peripheral signaling cascades that mediate inflammatory sensitization. For example, protein kinase C epsilon (PKCe), activated in response to β2-adrenergic receptor stimulation, is critical for sensitization in male, but not female, rats (Hucho, Dina, Kuhn, & Levine, 2006). This sex difference persists ex vivo as stimulating DRG neurons in culture with a β2-adrenergic receptor agonist activates PKCe only in male-derived cells. Further, estrogen application to male-derived DRG neurons prevents adrenergic receptor–mediated PKCe upregulation. This effect is rapid, which suggests it is not due to modification of gene transcription. Combined, these findings indicate that estrogen blocks engagement of PKCe-dependent pathways in the mediation of inflammatory pain (Hucho et al., 2006).
Sex differences are also reported in peripherally mediated opioid analgesia (Clemente, Parada, Veiga, Gear, & Tambeli, 2004). Formalin injections into the temporomandibular joint (TMJ) elicited pain behaviors—including rubbing of injected area and head flinches—in a dose-dependent manner in male and female rodents. Local injection of a kappa opioid receptor agonist into the TMJ reduced pain behaviors in both sexes, with a significantly greater effect in females (Clemente et al., 2004). Further, females in diestrus—as determined through estrus cycle tracking—are even more sensitive to kappa-mediated analgesia than females in proestrus. This analgesia is likely mediated through local activation of kappa receptors, given that injections of the agonist into the contralateral TMJ produced no effect on pain behaviors. Diestrus is characterized by relatively low levels of estradiol and progesterone, which could account for the potentiated response to kappa opioid–induced analgesia (Clemente et al., 2004).
Infiltration of immune cells into the DRG after PNI also showed sex differences (Lopes et al., 2017). Although similar levels of neutrophils, monocytes, and macrophages are detected in the DRG after injury in males and females, there is a difference in adaptive immune cell infiltration between females and males. Male mice are shifted toward a B-cell response, while females display increased infiltration of T cells (Lopes et al., 2017). Thus, peripheral adaptive immune responses in neuropathic pain could be sexually dimorphic.
Sex Differences in Spinal Pain Processing
Regarding sex differences in spinal pain processing, microglia in the spinal dorsal horn play important roles. They are key mediators of chronic pain hypersensitivity but only in males. In females microglia are dispensable but T lymphocytes appear to have a key role.
Spinal Microglia Are Key Mediators of Chronic Pain Hypersensitivity in Males
Microglia are the principal innate immune cells of the CNS (Salter & Stevens, 2017). They constitute 5–10% of cells in the brain and spinal cord and are responsible for ongoing surveillance of CNS tissue and maintenance of homeostasis. Microglia form a latticework of nonoverlapping cells throughout the CNS parenchyma, which allows for (p. 403) efficient detection of potential threats, such as infection, brain injury, or disease. Microglia may adopt a variety of morphological and functional phenotypes to adapt to specific conditions within the CNS (Salter & Beggs, 2014). These cells respond rapidly to direct CNS injury and inflammation. But microglia are more than just neuroinflammatory cells; they are integral regulators of many aspects of the healthy CNS. Indeed, microglia can regulate neuronal activity and are able to dampen the firing of highly active neurons. These functionally diverse cells have been implicated in synaptic development and plasticity, and dysfunction of (Salter & Stevens, 2017) microglia is implicated in many CNS disorders (Salter & Beggs, 2014).
A large body of evidence has demonstrated that microglia are critical in the development and maintenance of pain hypersensitivity evoked by PNI (Beggs, Trang, & Salter, 2012). A detailed pathway has been elucidated by which nerve injury in the periphery acts at a distance in the spinal cord to stimulate microglia, which then signal to neurons in lamina I of the dorsal horn to increase their firing through disinhibition. The studies through which this pathway was determined were all done using solely male rats or mice (see also the next section). A hallmark of the spinal changes induced by PNI is proliferation of microglia (Tsuda et al., 2003). But this proliferation, while striking, in and of itself is not sufficient to produce pain hypersensitivity, as has been repeatedly shown. Rather, PNI evokes key signaling changes within spinal microglia: upregulation of the purinergic receptor P2X4 (P2X4R), activation of p38 mitogen-activated protein kinase (p38 MAPK), and de novo synthesis and release of BDNF. Through a number of intermediaries, PNI stimulates production of P2X4Rs in microglia by upregulating a transcription factor cascade of interferon regulatory factor 8 (IRF8) and interferon regulatory factor 5 (IRF5) (Masuda et al., 2016). IRF5 binds directly to the P2rx4 promotor, stimulating transcription and ultimately translation of P2X4Rs. These receptors are then trafficked to the surface of the microglia, where they are activated by adenosine triphosphate (ATP), which has been shown to be released by intrinsic neurons in the dorsal horn (Masuda et al., 2016). Activating P2X4Rs, which are permeable to calcium, stimulates p38 MAPK, which in turns drives the de novo synthesis and release of BDNF (Trang, Beggs, Wan, & Salter, 2009).
BDNF is the critical signaling molecule from microglia to neurons. It acts through the tyrosine kinase receptor TrkB to elicit two major changes in lamina I neurons: disinhibition and facilitated excitation (Coull et al., 2005; X. J. Liu et al., 2008). Disinhibition is caused through TrkB-stimulated downregulation of the function and expression of potassium chloride cotransporter KCC2. KCC2 maintains a low intracellular Cl− level through driving chloride extrusion, which is necessary for effective GABAA receptor– and glycine receptor–mediated fast inhibitory transmission. The loss of KCC2 leads to elevated intracellular Cl−, thereby decreasing fast inhibition, termed disinhibition (Coull et al., 2003). TrkB signaling in lamina I neurons enhances excitation through potentiating NMDA receptor currents (Hildebrand et al., 2016). Activating TrkB stimulates the tyrosine kinase Fyn, which phosphorylates the GluN2B subunit of NMDARs, thereby potentiating receptor activity. Combined, disinhibition and potentiated excitation produce a state of hyperexcitability in lamina I neurons, unmasking normally silent (p. 404) low-threshold peripheral inputs to these neurons and increasing the transmission of nociceptive information to the brain (Keller, Beggs, Salter, & De Koninck, 2007). This neuronal hyperexcitability is characterized by responsiveness to previously nonnoxious stimuli, enhanced activity to noxious stimuli, as well as spontaneous firing. These changes in lamina I projection neurons may underlie the three cardinal neuropathic pain symptoms: allodynia, hyperalgesia, and spontaneous pain (Keller et al., 2007).
Sex Differences in the Role of Microglia in Chronic Pain Hypersensitivity
Until recently, studies investigating microglia and pain have used only male rodents, reflecting the generalized sex bias in preclinical pain research (Sorge et al., 2015). Interrogating the pathways so well characterized in males revealed profound sex differences in the role of microglia and glia/immune-neuron signaling in pain (Inyang et al., 2018; Sorge et al., 2011, 2015; Taves et al., 2015). The first evidence that microglia may play a different role in pain in females emerged after investigating toll-like receptor 4 (TLR4), a transmembrane protein that elicits innate immune cell activation in response to pathogens such as lipopolysaccharide (LPS)—in both sexes. Although TLR4 is expressed on various cell types throughout the body, in the spinal cord it is specifically expressed by microglia. Spinal TLR4s were found to contribute to both inflammatory and neuropathic pain signaling in male mice but not in females, where pain signaling was found to be independent of spinal TLR4s. Further, naïve female mice were nonresponsive to intrathecal injection of LPS, which by contrast caused development of robust pain hypersensitivity in males (Sorge et al., 2011). This sex difference was dependent on testosterone, as modulating testosterone levels affected sensitivity to intrathecal LPS in both sexes. Interestingly, the sex difference in TLR4 responses was spinal cord specific; injecting LPS into the brain or hind paw elicited pain hypersensitivity equally in males and females (Sorge et al., 2011).
Interrogating the microglia–neuronal signaling pathway, described previously, in female mice revealed a striking sex difference (Sorge et al., 2015). PNI elicited similar levels of behavioral sensitization in males and females, and the proliferation of microglia in the dorsal horn of the spinal cord was indistinguishable between the sexes. However, a series of behavioral experiments showed that neither microglia nor any aspect of microglial signaling (i.e., P2X4Rs, p38 MAPK and BDNF) was required for induction or maintenance of PNI-induced mechanical pain hypersensitivity in female mice (Sorge et al., 2015). A key piece of evidence is that in genetically engineered mice, induced knockout specifically of BDNF in microglia prevented, and also could reverse, the pain hypersensitivity in male mice, but not females (Sorge et al., 2015). In work by a different group using mice with diphtheria toxin receptor expressing CX3CR1+ cells, targeted microglial ablation alleviated mechanical hypersensitivity 7 days after PNI in male mice but not in females (Peng et al., 2016).
A subsequent study has found that the sex difference in microglial signaling was consistent across mice and rats (Mapplebeck et al., 2018). This study also showed that P2X4R protein levels were increased after PNI in male, but not female, rats, consistent with the (p. 405) gene expression data in mice. Further, loss of upregulation of P2X4Rs in females appeared to result from lack of binding of IRF5 to the P2rx4 promotor (Mapplebeck et al., 2018). Provocatively, intrathecally administrating ATP-stimulated microglia derived from males induced pain hypersensitivity in naïve rats of both sexes. Conversely, administrating female-derived microglia had no effect on pain behaviors in either sex. Despite the sex difference in upstream microglia signaling, NMDARs were required for PNI-induced pain hypersensitivity in both females and males (Sorge et al., 2015). Thus, females can respond to microglia and engage NMDARs, but in females the microglia pathway is blocked at the key step of transcriptional upregulation of P2X4Rs (Mapplebeck et al., 2018).
In terms of the signaling pathway upstream of neurons in females, evidence suggests that PNI-induced pain hypersensitivity—which is behaviorally indistinguishable in male and female rodents—depends on adaptive immune cells, possibly T cells (Sorge et al., 2015). Females have greater numbers of T cells in the spinal cord and circulatory system. Additionally, female mice lacking adaptive immune cells switch to the microglial-dependent pain signaling pathway, indicating that adaptive immune cells are necessary for suppressing the blockade P2X4R transcription. Also, agents that interfere with the function of adaptive immune cells suppressed PNI-induced hypersensitivity in females but not in males (Sorge et al., 2015). But which types of adaptive immune cells are responsible and how they signal to neurons in the dorsal horn remain major outstanding questions.
The body of evidence for sexual dimorphism in the involvement of microglia in pain hypersensitivity is growing (Inyang et al., 2018; Taves et al., 2015). For example, formalin-induced, as well as PNI-induced, pain hypersensitivity is dependent on spinal p38 MAPK in male, but not female, rodents (Taves et al., 2015). Microglia have also been implicated in maintaining bone cancer–induced pain hypersensitivity and hyperalgesia in female rats (Yang et al., 2015). Complete Freund’s adjuvant (CFA)–evoked inflammatory pain was also microglial dependent in male mice and microglial independent in females (Sorge et al., 2015). This sex difference in the mechanisms underlying inflammatory pain was dependent on testosterone, as testosterone manipulation triggers “switching” between pathways in both sexes. Microglia may, however, not be involved solely in males as microglial ablation in females, as well as in males, was found to reduce thermal pain hypersensitivity induced by PNI (Peng et al., 2016). Thus, we must caution against overgeneralization. Each pain hypersensitivity condition needs to be investigated for sex differences not only in the behavioral phenotypes but also in the underlying molecular and cellular signaling pathways.
Regulation of Descending Control by Sex
Descending projections from the PAG to the RVM and spinal cord dorsal horn constitute a major pain control pathway (Loyd et al., 2007, 2008; Loyd & Murphy, 2006). This descending pathway plays a critical role in analgesia elicited by either endogenous or (p. 406) exogenous opioids (Loyd et al., 2007, 2008; Loyd & Murphy, 2006). A number of sex differences in the PAG-RVM-spinal cord neural circuit, the majority of which have been studied in the context of morphine analgesia, have been described (Loyd et al., 2007, 2008; Loyd & Murphy, 2006).
Retrograde tracing has revealed that even the anatomy of the PAG-RVM-spinal cord neural circuit is sexually dimorphic. Females have more descending projections from the dorsomedial and lateral/ventrolateral PAG to the RVM than males under normal conditions (Loyd & Murphy, 2006). However, c-Fos staining has shown that CFA-induced inflammation recruits a higher percentage of PAG-RVM projection neurons in males (Loyd & Murphy, 2006). Thus, despite having more PAG-RVM output neurons, descending pain modulation may be less effective in females under pathological conditions (Loyd & Murphy, 2006).
Morphine has been widely shown to be more efficacious in relieving pain in males than in females, in both humans and rodents (Loyd & Murphy, 2006). Systemic morphine administration reduced c-Fos activation in the PAG after CFA in male, but not female, rats (Loyd & Murphy, 2006). Further, retrograde labeling combined with c-Fos staining in naïve rats has revealed that systemic morphine activated fewer PAG-RVM projections in females than in males (Loyd et al., 2007). There were also sex differences in PAG-RVM activity in response to chronic morphine exposure (Loyd et al., 2008). While morphine produced more analgesia in males, it also produced more tolerance in males; that is, morphine became less effective over repeated dosing. In male rats, activating the PAG-RVM neural circuit decreased during repeated morphine administration, corresponding to the development of tolerance. Thus, descending inhibition decreased in males with chronic morphine exposure, leading to a decrease in analgesic efficacy. Female rats, however, did not show any change in PAG-RVM activity, which is aligned with their minimal tolerance development (Loyd et al., 2008). These findings suggest that the differential levels of morphine-induced analgesia and tolerance in males as compared with females could be attributable to differences in PAG-RVM descending inhibition. Endogenous opioid regulation of PAG-RVM neural circuitry may be similarly sexually dimorphic, which could contribute to increased pain sensitivity and chronic pain risk in females.
Activity in descending inhibitory pathways may be regulated by testosterone levels, at least in females (Vincent et al., 2013). A functional magnetic resonance imaging (fMRI) study assessed women before and after administering the combined oral contraceptive pill, which produces a state of low endogenous estradiol and progesterone (Vincent et al., 2013). Behavioral testing during fMRI imaging found that women given the pill who had low testosterone were more sensitive to noxious stimuli. Interestingly, noxious stimuli-mediated activation of descending inhibitory pathways—including the RVM—was positively associated with testosterone levels. Thus, testosterone under low estradiol conditions may facilitate descending inhibition. If testosterone is a generalized enhancer of descending pain pathways, this could also account for the increased activity in PAG-RVM neural circuitry in males.
(p. 407) Where Pain, Sex, and Development Meet
The development of sex differences in pain biology has been traditionally assumed to be postpubertal, but insufficient research has been carried out in this area. In fact, sex differences in the role of microglia in chronic pain hypersensitivity are present from a very early age. Priming of adult pain sensitivity by early life injury is dependent on neonatal spinal microglial activation at the time of injury, but this is true only in males. Adult female pain behavior can be equally primed by injury soon after birth, but this does not require microglial activation (Moriarty et al., 2019). Hence, sex differences in microglial signaling have an early developmental onset.
The same is true of cortical pain networks, where any sex differences are commonly thought to be postpubertal and experience and context dependent. However, the magnitude and spatial distribution pattern of nociceptive activity in the human brain is sex dependent from birth. Spatially widespread pain (but not touch) event-related potentials are more common in newborn females, irrespective of gestational age, suggesting greater pain-related anatomical and functional connectivity in the female brain from an early developmental stage (Verriotis et al., 2018).
This chapter summarized the key roles played by developmental age and sex in nociception and pain. Where the two factors overlap in determining individual pain sensitivity and vulnerability to chronic pain is an area of future important research.
We thank Dr. Josiane Mapplebeck for assistance with an early draft of the sex difference section of this chapter.
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