Chapter 9 Potential role of stress systems in the pathogenesis of whiplash associated disorders

Consistent with the term ‘whiplash associated disorders’ (WAD), biological mechanisms influencing neck pain and coincident somatic symptoms after a motor vehicle crash (MVC) have traditionally been conceptualised as related to cervical sprain/strain during the MVC event. However, in addition to subjecting soft tissues to biomechanical strain, an MVC event is also an acute stressor that activates physiological stress response systems. It is increasingly appreciated that these systems modulate neurosensory processing and are capable of increasing pain sensitivity (causing hyperalgesia) and of causing normally non-painful sensations to become painful (causing allodynia). This chapter reviews the evidence that physiological systems involved in the stress response may contribute to the development of the hyperalgesia and allodynia seen in people with WAD after an MVC.

Several concepts are important when considering the potential role of stress systems in the development of WAD:

1. The term ‘stress systems’ refers to the physiological processes that modulate neurosensory processing when an organism experiences a stressful event, such as a potentially life-threatening MVC. These systems are extremely useful in optimising the response of an organism to immediate environmental circumstances. However, it appears that the activation of these potent modulatory systems may cause and/or contribute to hyperalgesia and allodynia, which are long-lasting and deleterious.

2. The available evidence suggests that stress system activation may, by itself, be capable of causing long-lasting changes in pain processing, even in the absence of tissue trauma. For example, in an animal model of stress exposure, exposing Sprague-Dawley rats to 10–20 minutes of forced swimming (inescapable, non-painful, moderate swim stress) for three days produced hyperalgesia to both thermal and chemical stimuli.¹ In vulnerable individuals, stress system activation in response to a potentially life-threatening MVC may, by itself, be sufficient to cause WAD symptoms.

3. The evidence also suggests that the influence of stress response system components on central nervous system (CNS) processes may be time-dependent. For example, since the middle of the last century, it has been appreciated that adrenergic nervous system activation can produce immediate analgesia.^2,³ Indeed, it is part of common lay understanding that such analgesia is a component of the ‘fight or flight’ response. In contrast, only during the past two decades have animal and human studies revealed that adrenergic nervous system activation may also cause marked hyperalgesia and allodynia.⁴^–¹⁰ These opposing effects of stress systems on neurosensory processing are consistent with recent work demonstrating the opposing, time-dependent effects of stress response elements on other CNS processes. For example, in order to form long-lasting memories (‘flashbulb memories’) of traumatic events, the same set of stress response effectors produces, first, a brief period of marked memory formation and then a period of marked memory inhibition.^11,¹²

In the sections that follow, the available evidence is reviewed regarding the potential influence of specific stress system components on neurosensory processing after stress exposure. It is hoped that, in aggregate, these data will support the plausibility of a contribution of stress systems to the alterations in neurosensory processing which characterise WAD. In the final sections, the potential clinical implications of these findings, as well as the current research needs and future directions, are discussed.

Sympathetic nervous system

Non-genetic studies

Acute stressors activate the sympathetic nervous system and adrenomedullary hormonal system, resulting in the release of adrenaline and noradrenaline.^13,¹⁴ These catecholamines produce immediate adaptive benefits, such as increased vigilance and energy mobilisation.^13,¹⁴ In addition, catecholamines have also long been known to be capable of producing immediate analgesia.^2,³ However, sympathetic activation can also have adverse consequences. For example, sympathetic activation in the setting of a surgical stressor has been shown to increase both immediate and long-term cardiovascular sequelae.^15,¹⁶ As described below, it is also being increasingly recognised that sympathetic activation may contribute to the development of hyperalgesia and allodynia after stressful events, such as an MVC.¹⁷

Catechol-O-methyltransferase (COMT) is the primary enzyme that degrades catecholamines. In animal studies, increasing catecholamine levels via the inhibition of this enzyme has been shown to produce allodynia and hyperalgesia.⁴ The increase in pain sensitivity produced by elevated catecholamines was found to be comparable in magnitude to that produced by the intraplantar injection of carrageenan (an inflammatory agent).⁴ Similarly, in humans the chronic administration of β–adrenergic receptor agonists has been shown to produce a painful arthritis-like syndrome.¹⁸

In addition to these direct effects on pain sensitivity, catecholamines have been shown to enhance pain due to tissue inflammation. In animal models of rheumatoid arthritis, the sustained bioavailability of adrenaline (either released from the adrenal medulla or administered exogenously) substantially augments inflammatory mediator-induced hyperalgesia.^5,⁶ Similarly, increasing catecholamine levels has been shown to increase carrageenan-induced pain.⁴

Just as increased catecholamines have been shown to increase pain, a reduction in catecholamine effects has been shown to reduce pain and/or prevent enhanced pain sensitivity. Denervation of sympathetic noradrenergic fibres and the depletion of peripheral adrenaline have been found to attenuate arthritic responses.^7,⁸ Nackley-Neely et al.⁴ showed that the allodynia and hyperalgesia induced by increasing catecholamine levels could be prevented by the administration of selective β₂ and β₃ antagonists. In humans, sympathetic blockade or the administration of the β-adrenergic receptor antagonist propranolol has been observed to reduce the severity of arthritis and joint responses to injury, and to provide pain relief for patients with chronic musculoskeletal pain syndromes.¹⁹^–²²

Genetic studies

Another way to assess the association between elevated catecholamine levels and vulnerability to develop immediate and persistent pain is to examine the association between genetic polymorphisms that determine adrenergic system function and patient outcomes. If adrenergic systems influence pain processing, then genetic variations influencing adrenergic system function may be associated with individual variation in pain sensitivity and vulnerability to develop persistent pain.

Catecholamine levels in the synaptic cleft are influenced by the activity of enzymes that degrade catecholamines. Such enzymes include COMT, which is located on the postsynaptic membrane, and monoamine oxidases A and B (MAO-A and MAO-B), which are located on the outer membrane of mitochondria in the presynaptic cell. Catecholamine concentrations are also influenced by the activity of transporters, such as the noradrenaline (norepinephrine) transporter (NET), which transports noradrenaline from the synaptic cleft to presynaptic storage vesicles for later use. If adrenergic pathways activated by the stress response influence pain processing, then genetic variations in COMT, MAO-A/B and NET may be associated with individual variation in pain sensitivity and vulnerability to develop persistent pain. The available evidence suggests that this is, indeed, the case, as outlined below.

• COMT: Previous work has identified three common variations, or haplotypes, of the COMT gene that code for different levels of enzymatic activity and are associated with differences in pain sensitivity.¹⁰ The LPS haplotype codes for the highest enzyme activity and is associated with the highest pain tolerance. The APS haplotype codes for comparably less enzyme activity and is associated with average pain tolerance. The HPS haplotype codes for the least enzyme activity and is associated with the lowest pain tolerance.¹⁰ In a recent prospective cohort study, the presence of even a single LPS haplotype was found to diminish, by as much as 2.3 times, the risk of developing a common musculoskeletal pain condition, myogenous temporomandibular joint disorder (TMD).¹⁰ Preliminary evidence also suggests that genetic variations in COMT function influence vulnerability to acute and chronic WAD symptoms after an MVC.²³

• MAO and NET: Polymorphisms of the gene encoding MAO-B, MAO-B, have been associated with pain intensity after tonsillectomy and third molar extraction.^24,²⁵ NET inhibition has been shown to alleviate mechanical allodynia²⁶ and to augment endogenous analgesia.²⁷ The analgesic affect of NET inhibition is believed to occur, at least in part, via bulbospinal noradrenergic projections that activate α_2A-adrenoreceptors in the spinal cord dorsal horn.^26,²⁸ The analgesia produced by several common analgesics is believed to be due, in part, to NET inhibition.^27,²⁹

Adrenergic receptors activate (transduce) the cellular response to catecholamines. If adrenergic pathways involved in the stress response influence pain sensitivity and vulnerability to develop persistent pain, then pain processing would also be expected to be influenced by the function of adrenergic receptors. The available evidence suggests that this is, indeed, the case, as outlined below.

• α₁-adrenoceptors: α₁-adrenoceptor activity has been shown to sensitise nociceptive neurotransmission at numerous CNS sites ³⁰ and to upregulate known pain and inflammatory mediators, such as STAT and cytokines.³¹ Consistent with these findings, α₁-adrenoceptor agonists, such as phenylephrine, generally have a pro-nociceptive effect.³²^–³⁸ α₁-adrenoceptors are subclassified as α_1A, α_1B and α_1D. α_1A and α_1D receptors have been shown to contribute to inflammatory pain³² and heat pain³⁹ sensitivity, respectively. In addition, the three α₁-adrenoceptor subtypes have been shown to be differentially expressed in response to painful nerve damage, suggesting that it is likely that nociceptive stimulation regulates the expression of these genes.⁴⁰ In a recent prospective study, genetic variations in α_1A receptors were found to be associated with up to a nine-fold increase in vulnerability to develop a common musculoskeletal pain condition, myogenous TMD.⁴¹ Further assessments of the influence of genetic variations in α_1A receptors on acute pain and vulnerability to persistent pain after an MVC are needed.

• α₂-adrenoceptors: α₂-adrenoceptor agonists, such as clonidine, are widely used as analgesics.⁴² α₂-adrenoceptors are subclassified as α_2A, α_2B and α_2C. α_2A receptors have received the most study, and have been shown to help mediate adrenergic antinociception.^43,⁴⁴ Little work has been done on examining the influence of specific α₂ genes on pain sensitivity, with the exception of a single study that found that variations in α_2A and α_2C receptors were associated with somatic symptom scores in patients with irritable bowel disease.⁴⁵

• β₂ and β₃ adrenoceptors: The β₂-adrenoceptor has received relatively more study, and has been associated with variation in nociceptive function.^9,⁴⁶ Cardiovascular function, particularly arterial blood pressure, appears to be regulated by β₂-adrenoceptors,⁴⁶ and cardiovascular and pain regulatory systems are closely associated with one another.^47,⁴⁸ A recent prospective study of the development of a common musculoskeletal pain disorder found that variation in the gene encoding the β₂-adrenoceptor is associated with vulnerability to develop persistent pain.⁹ In addition, a recent report identified an association between clinical conditions characterised by musculoskeletal pain and somatic symptoms and the minor allele for the gene encoding the β₃-adrenoceptor.⁴⁹ More work assessing the association between genetic variations influencing β₂ and β₃ adrenoceptor function and acute and persistent WAD symptoms after an MVC is needed.

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