David Finn
Professor of Pharmacology and Therapeutics, School of Medicine, Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, Ireland

https://doi.org/10.36866/pn.108.25

Pain and stress are two phenomena that most of us would rather not have to deal with throughout our lives! And yet both pain and stress have essential survival value for humans and other animals.

The ability to mount an appropriate response to stress is critical to allow us to cope with the physical and psychological challenges that life throws at us. Stress responses that are either sub-optimal or excessive can be maladaptive, leading to the development of illness, either physical or psychiatric (e.g. anxiety, depression). Pain, on the other hand, is an essential warning signal to potentially harmful or injury-producing stimuli. It facilitates learning in early life, and encourages rest and healing following injury. Its survival value is perhaps best illustrated through the very rare condition of congenital insensitivity to pain. Individuals with this condition are unable to feel pain from birth due to loss of function mutations in key proteins required for nociception (e.g. the sodium channel Nav1.7), but they typically die at a relatively young age due to an inability to detect and respond appropriately to critical illness, injury, or accumulation of injuries. However, while the ability to perceive acute pain is essential for survival, when pain persists longer than is physiologically necessary, it can become pathological and reduce quality of life. About 20% of the adult population of Europe have this type of chronic persistent pain (Breivik et al., 2006). Chronic pain is a complex and diverse disease state which can be very difficult to treat (about 40% of patients report their pain medication as inadequate; Breivik et al., 2006) and places a massive burden on the individual patient, on society, and on economies.

Stress-induced analgesia

Pain can be affected profoundly by stress. The impact of stress on pain usually depends on the nature, duration, and intensity of the stress, and also on the type of pain. Generally, stressors that are acute and intense, an immediate threat to homeostasis, result in a short-term suppression of pain known as stress-induced analgesia (Butler & Finn, 2009). Stress-induced analgesia has been widely studied and is part of the body’s defensive ‘fight or flight’ response. Thus, when a person is in a potentially dangerous situation, the body temporarily dampens down pain signalling in order to allow escape or coping, regardless of injury. A lot of good work over the past 50 years has illuminated our understanding of the physiology of this important form of endogenous analgesia. We know, for example, that it is mediated by activation of the descending inhibitory pain pathway. This pathway is comprised of neurons that project from higher cortical areas and the amygdala to the midbrain periaqueductal grey, which in turn projects to the rostral ventromedial medulla, from where neurons descend to the dorsal horn of the spinal cord. Activation of this descending pathway by stress or fear inhibits ascending nociceptive transmission. We also know from the pioneering early work of Akil, Madden, Patrick, Barchas, Fanselow, Liebeskind, and co-workers that stress-induced analgesia is mediated by the endogenous opioid system.

However, other neurotransmitter and neuropeptide systems also play a key role (e.g. GABA, glutamate, monoamines, cholecystokinin, the HPA axis, oxytocin). Indeed there are some forms of non-opioid-mediated stress-induced analgesia. Over the past 13 years or so, our group at the National University of Ireland (NUI) Galway, and other groups, have demonstrated a key role for the endogenous cannabinoid (endocannabinoid) system in mediating both conditioned (Butler et al., 2008; Finn et al., 2004; Olango et al., 2012) and unconditioned (Hohmann et al., 2005) stress-induced analgesia. In brief, stress or fear induce the on-demand synthesis and release of endogenous cannabinoid ligands (endocannabinoids) which then activate CB1 receptors in key sites throughout the descending inhibitory pain pathway, resulting in analgesia.

Stress-induced hyperalgesia

By contrast, exposure to prolonged/chronic stress or future-oriented anxiety or depression generally leads to hyperalgesia i.e. an exacerbation of pain, referred toas stress-induced hyperalgesia (Rhudy& Meagher, 2000). Stress-induced hyperalgesia is of clinical relevance, given that a high percentage of chronic pain patients have some form of stress-related psychiatric disorder. For example, patients with pain disorders are more likely to develop anxiety compared to the healthy population. Depression and chronic pain have been estimated to co-occur in up to 80% of patients, and the combination is more disabling and costlier to both patients and society than either disorder alone. In addition, experimental studies with healthy volunteers have shown that exposure to different stressors can alter how a person perceives pain (Rhudy & Meagher, 2000) and neuroimaging studies have shed light on the neural substrates involved in exacerbation of pain by stress or anxiety. Like stress-induced analgesia, animal models have played a key role in advancing our understanding of the receptor and neurochemical mechanisms that mediate stress-induced hyperalgesia (Corcoran et al., 2015; Jennings et al., 2014). It is clear that maladaptive changes in multiple receptors and neurotransmitter systems throughout stress- and pain-related circuitry are involved, includingthe opioid, GABA, glutamate, monoamine, cholecystokinin, and CRF signalling systems. More recently, we and others have also demonstrated that altered endocannabinoid system activity also underlies exacerbation of pain by stress or negative affect (Corcoran et al., 2015; Rea et al., 2014).

In summary, it is now very apparent that the neural basis for stress-induced modulation of pain lies in the fact that there is very considerable overlap in the neural substrates and circuitries of stress and pain.

Exacerbation of pain by stress, and co-morbidity of pain with stress-related psychiatric disorders including anxiety and depression represent very significant clinical challenges. Our ever-increasing understanding of overlap and interactions in the sites and mechanisms that regulate pain and stress means that it may be possible to develop new therapies which can treat both pain and co-occurring anxiety/depression. Indeed, the current use of drugs such as pregabalin and amitriptyline for the treatment of both pain and anxiety/depression illustrates the close associations that exist between pain and psychiatric disorders and suggests that novel drugs with improved efficacy and fewer adverse effects may eventually emerge from research focused on understanding stress–pain interactions.

References

Breivik H et al. (2006). Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 10, 287–333.

Butler RK & Finn DP (2009). Stress-induced analgesia. Prog Neurobiol 88, 184–202.

Butler RK et al. (2008). Endocannabinoid-mediated enhancement of fear-conditioned analgesia in rats: opioid receptor dependency and molecular correlates. Pain 140, 491–500.

Corcoran L et al. (2015). The role of the brain’s endocannabinoid system in pain and Its modulation by stress. Int Rev Neurobiol 125, 203–255.

Finn DP et al. (2004). Evidence for differential modulation of conditioned aversion and fear-conditioned analgesia by CB1 receptors. Eur J Neurosci 20, 848–852.

Hohmann AG et al. (2005). An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112.

Jennings EM et al. (2014). Stress-induced hyperalgesia. Prog Neurobiol 121, 1–18.

Olango WM & Finn DP (2013). Affective and cognitive modulation of pain. In: Allerton C (Ed), Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry, pp. 270–309.

Olango WM et al. (2012). The endocannabinoid system in the rat dorsolateral periaqueductal grey mediates fear-conditioned analgesia and controls fear expression in the presence of nociceptive tone. Br J Pharmacol 165, 2549–2560.

Rea K et al. (2014). Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli. Pain 155, 69–79.

Rhudy JL & Meagher MW (2000). Fear and anxiety: divergent effects on human pain thresholds. Pain 84, 65–75.