Repeated sound stress enhances inflammatory pain in the rat Sachia G. Khasar b,d , Paul G. Green b,d , Jon D. Levine a,b,c,d, * a Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0440, USA b Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440, USA c Division of Neuroscience & Biomedical Sciences Program, University of California at San Francisco, San Francisco, CA 94143-0440, USA d UCSF NIH Pain Center, University of California at San Francisco, Box 0440, C-522, 521 Parnassus Ave., San Francisco, CA 94143-0440, USA Received 27 January 2005; received in revised form 14 March 2005; accepted 29 March 2005 Abstract While it is well established that acute stress can produce antinociception, a phenomenon referred to as stress-induced analgesia, repeated exposure to stress can have the opposite effect. Since, chronic pain syndromes, such as fibromyalgia and rheumatoid arthritis, may be triggered and/or exacerbated by chronic stress, we have evaluated the effect of repeated stress on mechanical nociceptive threshold and inflammatory hyperalgesia. Using the Randall–Selitto paw pressure test to quantify nociceptive threshold in the rat, we found that repeated non-habituating sound stress enhanced the mechanical hyperalgesia induced by the potent inflammatory mediator, bradykinin, which, in normal rats, produces hyperalgesia indirectly by stimulating the release of prostaglandin E 2 from sympathetic nerve terminals. Hyperalgesia induced by the direct-acting inflammatory mediator, prostaglandin E 2 as well as the baseline nociceptive threshold, were not affected. Adrenal medullectomy or denervation, reversed the effect of sound stress. In sound stressed animals, bradykinin-hyperalgesia had a more rapid latency to onset and was no longer inhibited by sympathectomy, compatible with a direct effect of bradykinin on primary afferent nociceptors. In addition, implants of epinephrine restored bradykinin-hyperalgesia in sympathectomized non-stressed rats, lending further support to the suggestion that increased plasma levels of epinephrine can sensitize primary afferents to bradykinin. These results suggest that stress-induced enhancement of inflammatory hyperalgesia is associated with a change in mechanism by which bradykinin induces hyperalgesia, from being sympathetically mediated to being sympathetically independent. This sympathetic-independent enhancement of mechanical hyperalgesia is mediated by the stress-induced release of epinephrine from the adrenal medulla. q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Adrenal medulla; Bradykinin; Epinephrine; Fibromyalgia; Hyperalgesia; Pain 1. Introduction Studies have shown that acute stress increases nocicep- tive threshold (Jorum, 1988a; Mousa et al., 1981; Widy- Tyszkiewicz et al., 1995; Willer et al., 1981), leading to the suggestion that stress, in general, attenuates pain. However, available evidence suggests that repeated or prolonged stress can decrease nociceptive threshold (da Silva Torres et al., 2003a,b; Jorum, 1988a–c; Vidal and Jacob, 1982, 1986). Chronic, repeated stress activates the sympathoa- drenal stress axis (Black, 2002, 2003; Black and Garbutt, 2002; Pacak and Palkovits, 2001; Pacak et al., 1995), and the sympathoadrenal stress axis mediates vagotomy- induced enhancement of bradykinin-hyperalgesia (Khasar et al., 1998b). Vagotomy induces an increase in plasma epinephrine (Khasar et al., 2003b), and similar to vagotomy, prolonged administration of epinephrine enhances bradyki- nin-hyperalgesia (Khasar et al., 2003b). These observations strongly suggest that sustained increase in adrenal medulla- derived epinephrine contributes to the enhancement of bradykinin-hyperalgesia. Generalized chronic pain, as in patients with fibromyal- gia syndrome (FMS), has been suggested to involve the sympathoadrenal stress axis (Adler et al., 2002; Bradley and Pain 116 (2005) 79–86 www.elsevier.com/locate/pain 0304-3959/$20.00 q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2005.03.040 * Corresponding author. Address: UCSF NIH Pain Center, University of California at San Francisco, Box 0440, C-522, 521 Parnassus Ave., San Francisco, CA 94143-0440, USA. Tel.: C1 415 476 5108; fax: C1 415 476 6305. E-mail address: levine@itsa.ucsf.edu (J.D. Levine).