Elsevier

Progress in Neurobiology

Volume 121, October 2014, Pages 1-18
Progress in Neurobiology

Stress-induced hyperalgesia

https://doi.org/10.1016/j.pneurobio.2014.06.003Get rights and content

Highlights

  • Stress-induced hyperalgesia (SIH) is clinically relevant.

  • Stress is an important etiological factor for many chronic pain syndromes.

  • High comorbidity of stress-related psychiatric disorders and chronic pain.

  • Human and animal models have contributed significantly to our understanding of SIH.

  • Neuroanatomical, neurochemical and molecular alterations in brain and spinal cord underpin SIH.

Abstract

The importance of the modulation of pain by emotion is now widely recognised. In particular, stress and anxiety, depending on their nature, duration and intensity, can exert potent, but complex, modulatory influences typified by either a reduction or exacerbation of the pain state. Exposure to either acute or chronic stress can increase pain responding under experimental conditions and exacerbate clinical pain disorders. There is evidence that exposure to chronic or repeated stress can produce maladaptive neurobiological changes in pathways associated with pain processing, resulting in stress-induced hyperalgesia (SIH). Preclinical studies of SIH are essential for our understanding of the mechanisms underpinning stress-related pain syndromes and for the identification of neural pathways and substrates, and the development of novel therapeutic agents for their clinical management. In this review, we describe clinical and pre-clinical models used to study SIH and discuss the neural substrates, neurotransmitters and neuromodulatory systems involved in this phenomenon.

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).

References (216)

  • L.J. Bertoglio et al.

    Involvement of dorsolateral periaqueductal gray cholecystokinin-2 receptors in the regulation of a panic-related behavior in rats

    Brain Res.

    (2005)
  • S. Boccalon et al.

    Anxiety stress and nociceptive responses in mice

    Life Sci.

    (2006)
  • M.E. Bowers et al.

    Neuropeptide regulation of fear and anxiety: implications of cholecystokinin, endogenous opioids, and neuropeptide Y

    Physiol. Behav.

    (2012)
  • S. Bradesi et al.

    The role of neurokinin 1 receptors in the maintenance of visceral hyperalgesia induced by repeated stress in rats

    Gastroenterology

    (2006)
  • S. Bradesi et al.

    Dual role of 5-HT3 receptors in a rat model of delayed stress-induced visceral hyperalgesia

    Pain

    (2007)
  • N.N. Burke et al.

    Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions

    Neuroscience

    (2010)
  • N.N. Burke et al.

    Maternal deprivation is associated with sex-dependent alterations in nociceptive behavior and neuroinflammatory mediators in the rat following peripheral nerve injury

    J. Pain

    (2013)
  • I. Bushlin et al.

    Cannabinoid–opioid interactions during neuropathic pain and analgesia

    Curr. Opin. Pharmacol.

    (2010)
  • R.K. Butler et al.

    Stress-induced analgesia

    Prog. Neurobiol.

    (2009)
  • C. Caceres et al.

    Cardiovascular reactivity to psychological stress may enhance subsequent pain sensitivity

    Pain

    (1997)
  • X. Chen et al.

    Epinephrine-induced excitation and sensitization of rat C-fiber nociceptors

    J. Pain

    (2005)
  • X. Chen et al.

    Stress enhances muscle nociceptor activity in the rat

    Neuroscience

    (2011)
  • S. Chiba et al.

    Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2012)
  • E.K. Chung et al.

    Neonatal maternal separation enhances central sensitivity to noxious colorectal distention in rat

    Brain Res.

    (2007)
  • E.K. Chung et al.

    Visceral hyperalgesia induced by neonatal maternal separation is associated with nerve growth factor-mediated central neuronal plasticity in rat spinal cord

    Neuroscience

    (2007)
  • T.J. Connor et al.

    Forced swim test-induced neurochemical endocrine, and immune changes in the rat

    Pharmacol. Biochem. Behav.

    (1997)
  • A. Costa et al.

    Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats

    Neurosci. Lett.

    (2005)
  • I.L. Da Silva Torres et al.

    Long-lasting delayed hyperalgesia after chronic restraint stress in rats—effect of morphine administration

    Neurosci. Res.

    (2003)
  • A.J. Devall et al.

    Hyperalgesia in the setting of anxiety: sex differences and effects of the oestrous cycle in Wistar rats

    Psychoneuroendocrinology

    (2009)
  • A.J. Devall et al.

    Estrous cycle stage influences on neuronal responsiveness to repeated anxiogenic stress in female rats

    Behav. Brain Res.

    (2011)
  • A. Dhir et al.

    Venlafaxine reverses chronic fatigue-induced behavioral, biochemical and neurochemical alterations in mice

    Pharmacol. Biochem. Behav.

    (2008)
  • O.A. Dina et al.

    Enhanced cytokine-induced mechanical hyperalgesia in skeletal muscle produced by a novel mechanism in rats exposed to unpredictable sound stress

    Eur. J. Pain

    (2011)
  • L.M. Dufton et al.

    Effects of stress on pain threshold and tolerance in children with recurrent abdominal pain

    Pain

    (2008)
  • A. Dupen et al.

    Mechanisms of opioid-induced tolerance and hyperalgesia

    Pain Manag. Nurs.

    (2007)
  • M.J. Eaton et al.

    A single intrathecal injection of GABA permanently reverses neuropathic pain after nerve injury

    Brain Res.

    (1999)
  • D.P. Finn et al.

    Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats

    Neuropharmacology

    (2003)
  • D.A. Fishbain et al.

    Male and female chronic pain patients categorized by DSM-III psychiatric diagnostic criteria

    Pain

    (1986)
  • H. Flor et al.

    Effect of sensory discrimination training on cortical reorganisation and phantom limb pain

    Lancet

    (2001)
  • A.E. Friedrich et al.

    Modulation of visceral hyperalgesia by morphine and cholecystokinin from the rat rostroventral medial medulla

    Pain

    (2003)
  • A. Gadek-Michalska et al.

    Effect of repeated restraint on homotypic stress-induced nitric oxide synthases expression in brain structures regulating HPA axis

    Pharmacol. Rep.

    (2012)
  • G.D. Gamaro et al.

    The effects of acute and repeated restraint stress on the nociceptive response in rats

    Physiol. Behav.

    (1998)
  • G.H. Gameiro et al.

    The effects of restraint stress on nociceptive responses induced by formalin injected in rat's TMJ

    Pharmacol. Biochem. Behav.

    (2005)
  • G.H. Gameiro et al.

    Nociception- and anxiety-like behavior in rats submitted to different periods of restraint stress

    Physiol. Behav.

    (2006)
  • Y.J. Gao et al.

    Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats

    Pain

    (2004)
  • C.H. Gibbons et al.

    Experimental hypoglycemia is a human model of stress-induced hyperalgesia

    Pain

    (2012)
  • L.A. Grande et al.

    Complex regional pain syndrome as a stress response

    Pain

    (2004)
  • P.G. Green et al.

    Further validation of a model of fibromyalgia syndrome in the rat

    J. Pain

    (2011)
  • P.G. Green et al.

    Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat

    Pain

    (2011)
  • B. Greenwood-Van Meerveld et al.

    Stereotaxic delivery of corticosterone to the amygdala modulates colonic sensitivity in rats

    Brain Res.

    (2001)
  • T. Hata et al.

    Changes in CNS levels of serotonin and its metabolite in SART-stressed (repeatedly cold-stressed) rats

    Jpn. J. Pharmacol.

    (1991)
  • Cited by (0)

    View full text