Stress-induced analgesia
Introduction
Stress-induced analgesia (SIA) is an in-built mammalian pain suppression response that occurs during or following exposure to a stressful or fearful stimulus. Experimental models of this response help to elucidate the fundamental mechanisms of nociception and aversion as well as potential therapeutic targets for pain and stress-related disorders. The present manuscript is an update of earlier reviews on this topic published in the 1980s (Akil et al., 1986, Amit and Galina, 1986, Bodnar, 1986, Hayes and Katayama, 1986, Terman and Liebeskind, 1986, Terman et al., 1984). We include discussion of the most important findings pre-1986 together with extensive review of the body of work published on this topic since the mid-1980s. The manuscript will cover literature on the anatomical, neurochemical and molecular mechanisms underlying reduced nociceptive signaling following exposure to aversive stimuli. We will also highlight areas where further research is needed. We begin with an introduction to the evolutionary implications of the relationship between pain, stress and anxiety along with the genetics of SIA. Animal and human models employed to study stress- or fear-induced analgesia will then be reviewed followed by a description of the neuroanatomical substrates which have been shown to play a role in mediating and modulating endogenous analgesia through the descending inhibitory pain pathway. We then present the evidence for involvement of the opioid, GABAergic, glutamatergic, monoaminergic and cannabinergic systems in stress- or fear-induced analgesia. The review concludes with a discussion of the importance of this phenomenon in the pre-clinical study of the fundamental mechanisms of pain and fear/anxiety/stress and its potential clinical significance.
Section snippets
The evolutionary perspective and genetics of stress-induced analgesia
Pain can be considered as an evolutionarily developed defence response to an aversive or noxious stimulus. Aversive behaviours (e.g. fear, anxiety, panic), or behaviours to avoid pain, may be viewed as part of an organism's defence system against stimuli that could cause pain (Bolles and Fanselow, 1980). Thus, nociception and aversion have overlapping characteristics. The overlap is readily apparent at the neural pathway and substrate level.
Historically, pain and aversion have been studied as
Models of stress-induced analgesia (SIA)
Research into the mechanisms of SIA elucidates the complex physiological mechanisms of pain, stress, and fear while at the same time identifying potential new therapeutic targets for disorders associated with these phenomena. The next section will review models of SIA including unconditioned SIA and conditioned SIA (also known as conditional analgesia or fear-conditioned analgesia; FCA) as well as some models of distraction-induced analgesia where appropriate.
Neural substrates involved in SIA
In the 17th century, René Descartes proposed a “specificity theory” which stated that pain intensity and tissue damage are directly related. This theory was generally accepted for many years despite the fact that pain could be modulated by many factors, including experience and emotional state, and the existence of phantom-limb pain in amputees. The gate-control theory, first described by Melzack and Wall (1962), postulated that pain is modulated by the interaction between neurons at the spinal
Neurochemistry of SIA
The differences in the mechanisms of descending facilitation versus inhibition of nociception lie mostly in the activation of receptor subtypes coupled to different intracellular signal transduction mechanisms (for review see Millan, 2002). Neurotransmitters or neuropeptides which may either facilitate or inhibit nociception include serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, dopamine, dynorphin, acetylcholine, and nitric oxide (Akil et al., 1972, Behbehani, 1982, Cruz and Basbaum,
Clinical implications of SIA and concluding remarks
Any thorough understanding of fundamental physiological processes such as pain requires an understanding of internal, evolutionarily developed modulating mechanisms. Studies of SIA have intertwined two highly important adaptive and survival responses in mammals. Furthermore, the revelation that pain can be naturally suppressed leads to the speculation that manipulation of the mechanisms of SIA could lead to therapies for pain disorders, hopefully without the need for the aversive aspect of SIA.
Acknowledgement
This work was supported by a grant from Science Foundation Ireland.
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