Stress-induced hyperalgesia
Introduction
The last couple of decades have witnessed an emerging and sustained interest among research scientists and clinicians in understanding the interactions between stress and pain. This interest has been driven by overwhelming clinical and preclinical evidence demonstrating complex and potent effects of stress on pain processing and responding. Critical scrutiny of these data suggests that the nature, duration and intensity of the stressor are key determinants of the effects of stress on pain. Numerous studies have demonstrated that exposure to an acute, robust, intense stress induces a reduction in pain responding, a phenomenon described as stress-induced analgesia (for review see Butler and Finn, 2009).
On the other hand, repeated or chronic exposure to physical or psychological stressors which may be anticipatory/anxiogenic in nature, typically results in the less well understood phenomenon of stress-induced hyperalgesia (SIH) in humans (Crettaz et al., 2013; Gibbons et al., 2012, Kuehl et al., 2010; Rhudy and Meagher, 2000), and rodents (Andre et al., 2005, Bardin et al., 2009, Dina et al., 2011, Khasar et al., 2009, Le Roy et al., 2011, Quintero et al., 2011). Furthermore, it is widely documented that stress exacerbates existing pain associated with chronic pain disorders. Thus, stress is an important etiological factor for chronic pain disorders such as shoulder/neck pain syndrome, complex regional pain syndrome and fibromyalgia (Van Houdenhove and Luyten, 2006, Davis et al., 2011, Nilsen et al., 2007, Grande et al., 2004). These findings lend credence to the concept of SIH as a clinically relevant phenomenon, manifesting in a diverse array of stress-related pain disorders including inflammatory bowel disease, fibromyalgia and complex regional pain syndrome (Aaron and Buchwald, 2003, Egle and van Houdenhove, 2006, Grande et al., 2004, Walker et al., 2012). However, fewer studies have investigated the neurobiological mechanisms underpinning SIH.
A particular area of clinical interest within the context of stress-pain interactions is the comorbidity between chronic pain and affective disorders. The findings from numerous studies indicate a very high prevalence of comorbid chronic pain and psychiatric disorders such as anxiety and depression (Asmundson and Katz, 2009, Bair et al., 2003). Chronic pain patients are more likely to present with depression (21.7% vs. 10.0%) or anxiety disorders (35.1% vs. 18.1%) when compared to the general population (McWilliams et al., 2003). The prevalence of clinical anxiety among the population with chronic pain may be as high as 60%, with generalised anxiety disorder being the anxiety disorder that is most prevalent with chronic pain (Fishbain et al., 1986). The co-occurrence of anxiety and/or depression with chronic pain amplifies the negative effects of each alone, often complicating the treatment and resulting in poor outcome (Asmundson and Katz, 2009, Bair et al., 2003, Lieb et al., 2007). The relationship between altered emotional states and chronic pain disorders is complex and it is difficult to establish whether chronic pain leads to altered emotional states or whether the affective disorder predisposes an individual to the development of a pain disorder. For example, it has been reported that 77% of subjects who met criteria for generalised anxiety disorder comorbid with a pain condition, developed the disorder before the onset of chronic pain (Knaster et al., 2011). Taken together, these findings suggest a reciprocal relationship between chronic pain and affective disorders and support the concept of a self-perpetuating cycle of events that may underpin the chronic nature of such comorbid disorders.
In the present manuscript, we aim to provide a comprehensive review and critical analysis of the current understanding of SIH at pre-clinical and clinical levels. The neuroanatomical alterations associated with SIH, as revealed by both studies in human subjects and animal models will be discussed, as will the role of various neurotransmitter and neuromodulatory systems, including the opioidergic, gamma-aminobutyric acid (GABA)ergic, glutamatergic, monoaminergic, endocannabinoid and sympathetic adrenomedullary systems and the hypothalamo-pituitary-adrenal (HPA) axis.
Section snippets
Human models
The high prevalence of comorbid psychiatric and chronic pain states, and the reciprocal relationship which they share, suggests the involvement of common neural substrates and mechanisms in the modulation of pain and emotional states. In addition, the current use of drugs such as pregabalin, amitriptyline and duloxetine for the treatment of both pain and anxiety/depression further illustrates the close associations that exist between pain and affective disorders. Increased understanding of
Neural substrates of SIH
Multiple brain regions are engaged in a complex manner to mediate the experience of pain. Following exposure to a noxious stimulus, nociceptive information is transmitted via the ascending pain pathway to the somatosensory cortex, facilitating perception of pain. Subsequently, descending facilitatory or inhibitory pathways may be activated to potentiate or inhibit nociceptive transmission, respectively (Millan, 2002). Nociceptive transmission can be influenced by stress, through stress-induced
Neurotransmitters and neuromodulatory systems involved in SIH
Neurotransmitters, neuropeptides and other neuromodulators play a key role in both stress and pain processing within the CNS. As a consequence, pathophysiological alterations or adaptations in the levels of these neurochemicals could influence the outcome of stress-pain interactions. This section will discuss the evidence for involvement of key neurotransmitter and neuroendocrine systems (opioid, glutamate, GABA CCK, monoamines, endocannabinoid, HPA axis and the sympathetic adrenomedullary
Conflict of interest
None.
Acknowledgement
This work was supported by a grant from Science Foundation Ireland (10/IN.1/B2976).
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