COMMENTARY
Pain, Hyperalgesia and Stress Accepted for publication 9 March 2015 doi:10.1002/ejp.701
In this issue you will find a paper by Hoheisel et al., entitled “Immobilisation stress sensitizes rat dorsal horn neurons having input from the low back”. Environmental and bodily events perceived as threatening to the physical and psychological integrity of the body are experienced as stress if one is not able to cope with these situations. This state is expressed in reactions of the autonomic nervous system and neuroendocrine systems and of their effector tissues including the immune system. These reactions as well as the resulting interoceptive feelings of the body are generated by the brain. They are coordinated reactions to protect the homoeostatic regulation of body functions against disintegration. These coordinated autonomic, neuroendocrine and somatic motor reactions are accompanied by hypoalgesia or hyperalgesia during acute challenges. Both acute stress-induced hypoalgesia as well as hyperalgesia are evolutionary adaptive. During imminent threat from outside of the body, hypoalgesia promotes successful defence (“fight and flight”) behaviour. During real or pending injury of the deep somatic or visceral body domains, hyperalgesia promotes hypervigilance to somatic threats, to prevent further injuries, as well as wound healing and recuperative behaviour (Rhudy et al., 2013). Using a neurophysiological approach in anaesthetized rats, Hoheisel and coworkers tested the hypothesis that chronic stress enhances, in second-order neurons in the spinal dorsal horn, the resting activity and the responses to noxious stimulation of deep somatic tissues probably without sensitization of deep somatic nociceptive afferent neurons. The stress consisted of immobilization of the rats in a narrow tube for 1 hour per day over 12 consecutive days. This stress paradigm corresponds to psychological stress in humans. The control rats were either handled only (but not immobilized) or neither handled nor immobilized. The dorsal horn neurons were recorded in the lumbar segment L2 receiving their synaptic input from the caudal back muscles and the overlying fascia. Most of these dorsal horn neurons were located in the lamina IV to VI and were
© 2015 European Pain Federation - EFICâ
wide-dynamic-range neurons; thus, they had low mechanical thresholds and showed graded responses to noxious stimuli. The main results obtained in the chronically stressed rats, compared to the control rats, are that dorsal horn neurons, which are potentially involved in deep somatic nociception, first, exhibit new deep somatic receptive fields; second, exhibit stronger responses to physiological stimulation of deep somatic tissues; and third, develop resting activity or exhibit an increase in resting activity. Thus, these dorsal horn neurons behave as if sensitized during deep somatic inflammation. Interestingly, the rate of resting activity in the dorsal horn neurons of chronically stressed rats was considerably higher than in rats with chronically sensitized muscle nociceptors generated by complete Freund0 s adjuvant or nerve growth factor (see references in Hoheisel et al., 2015). Surprisingly, the pain pressure threshold of the low back did not change in the chronically stressed rats, yet they showed signs of increased anxiety in the open field test. The results are important. They may open an avenue to better understanding the mechanisms underlying chronic widespread pain, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic low back pain and other chronic pains such as pain in the posttraumatic stress disease, all these pains being located in the deep somatic body tissues or the viscera. These chronic pains are not primarily linked to sensitization of afferent nociceptive neurons. What are the mechanisms underlying the results of Hoheisel and coworkers? Chronic immobilization stress certainly activates the hypothalamic–pituitary– adrenal system as shown by Hoheisel and coworkers: the level of corticosterone metabolites significantly increased in the faeces of the rats. In parallel, the endogenous control system of nociception that is located in the lower and upper brain stem and under complex cortical control may shift in its balance between inhibition and excitation from an inhibitory (antinociceptive) mode to an excitatory (pronociceptive) mode. Furthermore, the sympatho-adrenal
Eur J Pain 19 (2015) 741--742
741
Commentary
system may be chronically activated with release of adrenaline by the adrenal medulla leading to a longlasting increase in adrenaline in the circulation. Experiments in Jon Levine0 s laboratory have shown in rats that long-lasting increase in plasma adrenaline (by chronic activation of the adrenal medulla, e.g. after subdiaphragmatic vagotomy) is followed by a strong decrease in paw-withdrawal threshold to mechanical stimulation of the hindpaw and strong enhancement of bradykinin-induced mechanical hyperalgesic behaviour, indicating indirectly that the nociceptors are sensitized by adrenaline. This sensitization develops over 3–14 days and is b2-adrenoceptor-mediated (see J€ anig, 2009). The interesting experimental work of Hoheisel and coworkers reported here invites further experimentation on the spinal dorsal horn neurons concentrating on the type of dorsal horn neuron (neurons projecting to supraspinal centres, interneurons, propriospinal neurons), on neurons in the superficial laminae I and II, on the effects of endogenous control systems on these neurons, etc. It would be interesting to know whether this type of immobilization stress
742 Eur J Pain 19 (2015) 741--742
generates a chronic increase in the concentration of adrenaline in the circulation. This could generate a long-term sensitization of nociceptors in the deep somatic tissues (skeletal muscle, joints and fascia). W. J€ anig Physiologisches Institut, Christian-AlbrechtsUniversit€ at zu Kiel, Germany Correspondence Wilfrid J€ anig E-mail: [email protected]
References Hoheisel, U., Vogt, M.A., Palme, R., Grass, P., Mense, S. (2015). Immobilisation stress sensitises dorsal horn neurons having input from the low back. Eur J Pain, 19, 861–870. J€anig, W. (2009). Autonomic nervous system and pain. In Science of Pain, A.I. Basbaum, M.C. Bushnell, eds. (San Diego: Academic Press) pp. 193–225. Rhudy, J.L., Bartley, E.J. and Palit, S. (2013). Stress and pain. In Encyclopedia of Pain, 2nd edition, G.F. Gebhart and R.F., Schmidt, eds. (Berlin: Springer) pp. 3718–3725.
© 2015 European Pain Federation - EFICâ
Pain, Hyperalgesia and Stress Accepted for publication 9 March 2015 doi:10.1002/ejp.701
In this issue you will find a paper by Hoheisel et al., entitled “Immobilisation stress sensitizes rat dorsal horn neurons having input from the low back”. Environmental and bodily events perceived as threatening to the physical and psychological integrity of the body are experienced as stress if one is not able to cope with these situations. This state is expressed in reactions of the autonomic nervous system and neuroendocrine systems and of their effector tissues including the immune system. These reactions as well as the resulting interoceptive feelings of the body are generated by the brain. They are coordinated reactions to protect the homoeostatic regulation of body functions against disintegration. These coordinated autonomic, neuroendocrine and somatic motor reactions are accompanied by hypoalgesia or hyperalgesia during acute challenges. Both acute stress-induced hypoalgesia as well as hyperalgesia are evolutionary adaptive. During imminent threat from outside of the body, hypoalgesia promotes successful defence (“fight and flight”) behaviour. During real or pending injury of the deep somatic or visceral body domains, hyperalgesia promotes hypervigilance to somatic threats, to prevent further injuries, as well as wound healing and recuperative behaviour (Rhudy et al., 2013). Using a neurophysiological approach in anaesthetized rats, Hoheisel and coworkers tested the hypothesis that chronic stress enhances, in second-order neurons in the spinal dorsal horn, the resting activity and the responses to noxious stimulation of deep somatic tissues probably without sensitization of deep somatic nociceptive afferent neurons. The stress consisted of immobilization of the rats in a narrow tube for 1 hour per day over 12 consecutive days. This stress paradigm corresponds to psychological stress in humans. The control rats were either handled only (but not immobilized) or neither handled nor immobilized. The dorsal horn neurons were recorded in the lumbar segment L2 receiving their synaptic input from the caudal back muscles and the overlying fascia. Most of these dorsal horn neurons were located in the lamina IV to VI and were
© 2015 European Pain Federation - EFICâ
wide-dynamic-range neurons; thus, they had low mechanical thresholds and showed graded responses to noxious stimuli. The main results obtained in the chronically stressed rats, compared to the control rats, are that dorsal horn neurons, which are potentially involved in deep somatic nociception, first, exhibit new deep somatic receptive fields; second, exhibit stronger responses to physiological stimulation of deep somatic tissues; and third, develop resting activity or exhibit an increase in resting activity. Thus, these dorsal horn neurons behave as if sensitized during deep somatic inflammation. Interestingly, the rate of resting activity in the dorsal horn neurons of chronically stressed rats was considerably higher than in rats with chronically sensitized muscle nociceptors generated by complete Freund0 s adjuvant or nerve growth factor (see references in Hoheisel et al., 2015). Surprisingly, the pain pressure threshold of the low back did not change in the chronically stressed rats, yet they showed signs of increased anxiety in the open field test. The results are important. They may open an avenue to better understanding the mechanisms underlying chronic widespread pain, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic low back pain and other chronic pains such as pain in the posttraumatic stress disease, all these pains being located in the deep somatic body tissues or the viscera. These chronic pains are not primarily linked to sensitization of afferent nociceptive neurons. What are the mechanisms underlying the results of Hoheisel and coworkers? Chronic immobilization stress certainly activates the hypothalamic–pituitary– adrenal system as shown by Hoheisel and coworkers: the level of corticosterone metabolites significantly increased in the faeces of the rats. In parallel, the endogenous control system of nociception that is located in the lower and upper brain stem and under complex cortical control may shift in its balance between inhibition and excitation from an inhibitory (antinociceptive) mode to an excitatory (pronociceptive) mode. Furthermore, the sympatho-adrenal
Eur J Pain 19 (2015) 741--742
741
Commentary
system may be chronically activated with release of adrenaline by the adrenal medulla leading to a longlasting increase in adrenaline in the circulation. Experiments in Jon Levine0 s laboratory have shown in rats that long-lasting increase in plasma adrenaline (by chronic activation of the adrenal medulla, e.g. after subdiaphragmatic vagotomy) is followed by a strong decrease in paw-withdrawal threshold to mechanical stimulation of the hindpaw and strong enhancement of bradykinin-induced mechanical hyperalgesic behaviour, indicating indirectly that the nociceptors are sensitized by adrenaline. This sensitization develops over 3–14 days and is b2-adrenoceptor-mediated (see J€ anig, 2009). The interesting experimental work of Hoheisel and coworkers reported here invites further experimentation on the spinal dorsal horn neurons concentrating on the type of dorsal horn neuron (neurons projecting to supraspinal centres, interneurons, propriospinal neurons), on neurons in the superficial laminae I and II, on the effects of endogenous control systems on these neurons, etc. It would be interesting to know whether this type of immobilization stress
742 Eur J Pain 19 (2015) 741--742
generates a chronic increase in the concentration of adrenaline in the circulation. This could generate a long-term sensitization of nociceptors in the deep somatic tissues (skeletal muscle, joints and fascia). W. J€ anig Physiologisches Institut, Christian-AlbrechtsUniversit€ at zu Kiel, Germany Correspondence Wilfrid J€ anig E-mail: [email protected]
References Hoheisel, U., Vogt, M.A., Palme, R., Grass, P., Mense, S. (2015). Immobilisation stress sensitises dorsal horn neurons having input from the low back. Eur J Pain, 19, 861–870. J€anig, W. (2009). Autonomic nervous system and pain. In Science of Pain, A.I. Basbaum, M.C. Bushnell, eds. (San Diego: Academic Press) pp. 193–225. Rhudy, J.L., Bartley, E.J. and Palit, S. (2013). Stress and pain. In Encyclopedia of Pain, 2nd edition, G.F. Gebhart and R.F., Schmidt, eds. (Berlin: Springer) pp. 3718–3725.
© 2015 European Pain Federation - EFICâ
