Repeated sound stress enhances inflammatory pain in the rat

Pain 116 (2005) 79–86 www.elsevier.com/locate/pain

Repeated sound stress enhances inflammatory pain in the rat Sachia G. Khasarb,d, Paul G. Greenb,d, Jon D. Levinea,b,c,d,* a Department of Medicine, University of California at San Francisco, San Francisco, CA 94143-0440, USA 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 b

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 E2 from sympathetic nerve terminals. Hyperalgesia induced by the direct-acting inflammatory mediator, prostaglandin E2 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 nociceptive threshold (Jorum, 1988a; Mousa et al., 1981; WidyTyszkiewicz 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,

* 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: [email protected] (J.D. Levine).

1986). Chronic, repeated stress activates the sympathoadrenal stress axis (Black, 2002, 2003; Black and Garbutt, 2002; Pacak and Palkovits, 2001; Pacak et al., 1995), and the sympathoadrenal stress axis mediates vagotomyinduced 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 bradykinin-hyperalgesia (Khasar et al., 2003b). These observations strongly suggest that sustained increase in adrenal medulladerived epinephrine contributes to the enhancement of bradykinin-hyperalgesia. Generalized chronic pain, as in patients with fibromyalgia syndrome (FMS), has been suggested to involve the sympathoadrenal stress axis (Adler et al., 2002; Bradley and

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

80

S.G. Khasar et al. / Pain 116 (2005) 79–86

McKendree-Smith, 2002; Bradley et al., 2002; Buskila, 2000; Cohen et al., 2000; Staud and Smitherman, 2002; Yunus, 2002). It has also been shown that women with FMS are more vulnerable to negative social stresses and experience more prolonged stress-related increases in pain (Davis et al., 2001). Indeed, recurrent daily stresses, such as loud noise, bright lights or poor sleep, commonly have a significant negative impact on FMS patients. Stress has also been found to aggravate and possibly contribute to the etiology of other chronic painful disorders, such as rheumatoid arthritis and irritable bowel syndrome (Cleare, 2004; Davis et al., 2001; Herrmann et al., 2000; Hudson et al., 2003), which are associated with an increased incidence of FMS (Alagiri et al., 1997; Buskila, 2001; Hudson et al., 2003; Naranjo et al., 2002; Triadafilopoulos et al., 1991; Waylonis and Heck, 1992; Wolfe and Michaud, 2004), referred to as secondary fibromyalgia. Since, the rat model of repeated non-habituating sound stress has been shown to activate the sympathoadrenal stress axis (Strausbaugh et al., 2003) and increase plasma epinephrine (Green and Levine, 2005), we have employed it to test the hypothesis that repeated sound stress can enhance mechanical pain.

2. Methods Nociceptive testing was performed on lightly restrained male (250–380 g) Sprague–Dawley rats (Charles River, Hollister, CA). Animals were housed in the Laboratory Animal Resource Center at the University of California, San Francisco, under a 12-h light/dark cycle. Experimental protocols were approved by the University of California, San Francisco Committee on Animal Research and conformed to NIH guidelines for care and use of experimental animals. Efforts were made to minimize discomfort to animals. The determination of the paw-withdrawal threshold, using an Ugo Basile Analgesymeter (Stoelting, Chicago, IL), and drug injection protocols were performed as described in previous experiments (Khasar et al., 2003a,b; Taiwo et al., 1987, 1989a,b). Bradykinin (0.1–1000 ng) and prostaglandin E2 (PGE 2) (1–1000 ng), two potent hyperalgesic inflammatory mediators, each was injected intradermally, into the dorsum of the hind paw, in a volume of 2.5 ml. Latency to onset of bradykinin-hyperalgesia in sound stressed or sham stressed control rats was done by injecting bradykinin (1 mg) and taking the paw-withdrawal measurements at 1-min intervals for the first 5 min, at 10 min and then at 10-min intervals until 30 min after injection. As in our previous studies (Aley et al., 1998, 2000; Dina et al., 2000, 2003; Joseph et al., 2003; Khasar et al., 1998b, 1999), the current experiments were not done blind. Surgical procedures. All surgical procedures were performed on rats under isoflurane (Abbot Laboratories, North Chicago, IL) anesthesia. Adrenal medullectomy (AMedx). To excise the adrenal medullae, the adrenal glands were located through a lateral incision in the abdominal wall, the capsule of the gland cut open and the adrenal medulla removed (Miao et al., 1992; Wilkinson et al., 1981). Rats were given 0.45% saline to drink, in place of

water, for the first 7 days after surgery. Adrenal medullectomy was performed at least 5 weeks prior to mechanical nociceptive testing. The 5-week post-surgical period was employed to allow hypothalamo-pituitary-adrenal axis function to recover (Wilkinson et al., 1981). Denervation of the adrenal gland (AMdenerv). The greater splanchnic nerve, the adrenal nerves innervating the adrenal gland, the suprarenal ganglion and the connection to the celiac ganglion were exposed using a retroperitoneal approach, through a lateral incision in the abdominal wall (Araki et al., 1984; Celler and Schramm, 1981). All connections of the suprarenal ganglion were cut, the ganglion removed and the surgical wound closed. Postoperative recovery of the rats was uneventful. Mechanical nociceptive testing was started 5 weeks post-surgery to allow for the same timing as in adrenal medullectomy. Sympathectomy. Complete sympathetic denervation of the hind limbs was carried out as previously described (Baron and Ja¨nig, 1988; Baron et al., 1988). Briefly, the sympathetic chains, from L1 to L4 ganglia, were surgically removed, bilaterally, via a lateral, extraperitoneal approach. Sound stress was initiated 7 days after surgery. 2.1. Sound stress Sound stress was performed as previously described (Strausbaugh et al., 2003). Animals were placed in a 12!15!9.5-in. wire mesh cage, which was kept 10 in. below a speaker, inside a 22! 22!28-in. sound-insulated box. The box was closed and animals were exposed to a 105 dB tone of mixed frequencies, ranging from 11 to 19 kHz. A 5- or 10-s tone was presented every minute, at random times during the minute, for a period of 30 min. This sound protocol was done on days 1, 3, and 4 and rats were used in nociceptive studies 24 h after the last exposure to sound stress. Sham stressed animals were also kept in the box for a period of 30 min, except that the sound was not switched on. 2.2. Chronic administration of epinephrine To address the possibility that increased plasma levels of epinephrine can sensitize primary afferents to the effect of bradykinin, we administered epinephrine to sympathectomized rats over a period of 7 days, using Alzetw micro-osmotic pumps (Durect Corporation, Cupertino, CA), Model 1007D, designed to deliver drug for 7 days at the rate of 0.5 ml/h. Pumps were implanted subcutaneously in the interscapular region. Epinephrine was given at the rate of 5.4 mg/h (Racotta et al., 1986) to sympathectomized rats. Rats receiving epinephrine were used on day 7 following the implanting of the pumps, counting the day of implantation as day 0. 2.3. Drugs The drugs used in the experiments were: (K)-epinephrine bitartrate, prostaglandin E2 (Sigma, St Louis, MO), and bradykinin (MP Biomedicals, Aurora, OH). Epinephrine was dissolved in 0.9% saline containing 1 mg/ml ascorbic acid and loaded in Alzetw micro-osmotic pumps. Bradykinin was dissolved in 0.9% saline. Stock solution of PGE2 (4 mg/ml) was made in 10% ethanol. Subsequent dilutions were made in 0.9% saline.

S.G. Khasar et al. / Pain 116 (2005) 79–86

2.4. Statistical analyses Data are presented as meanGSEM. Each figure or figure panel was analyzed separately, using two-way repeated measures analysis of variance (ANOVA), with one within-subjects factor (i.e. Dose) and one between-subjects factor (i.e. treatment). In Figs. 2 and 4, Scheffe´’s post hoc test was used to determine the basis for the between-subjects significant differences. Baseline paw-withdrawal thresholds were compared using the Student’s t-test. P!0.05 was the accepted level for statistical significance.

3. Results 3.1. Effect of repeated sound stress on bradykinin and PGE2 hyperalgesia Since, stress increases plasma epinephrine levels and sustained high levels of plasma epinephrine enhance bradykinin-hyperalgesia, we tested the hypothesis that repeated sound stress would enhance bradykinin-hyperalgesia. Bradykinin-hyperalgesia was significantly enhanced in sound stressed animals, compared to controls ((F(1,120)Z30.94, P!0.001); Fig. 1A). Sound stress did not, however, affect baseline nociceptive threshold (sound stress, 110.1G2.0 g (nZ24); sham stress, 109.7C1.0 g (nZ24); PZ0.855). Since, bradykinin has been shown to produce hyperalgesia by releasing PGE2 from post-ganglionic sympathetic neuron (Lembeck et al., 1976; Levine et al., 1986; Taiwo and Levine, 1988; Taiwo et al., 1990), we determined if intradermal injection of PGE2 would also enhance hyperalgesia in sound stressed rats. PGE2 induced dose-dependent hyperalgesia in sound stressed rats, that was not

81

significantly different from that in sham-stressed control rats ((F(1,66)Z3.70, PZ0.07); Fig. 1B). 3.2. Effect of lumbar sympathectomy In unstressed control rats, bradykinin-hyperalgesia is markedly attenuated following lumbar sympathectomy (Khasar et al., 1998a, 2002; Levine et al., 1986; Taiwo et al., 1990). To address the mechanism by which sound stress enhances bradykinin-hyperalgesia, we evaluated the effect of lumbar sympathectomy on bradykinin-hyperalgesia in sound stressed animals. Although there was an overall significant difference between the groups (F(2,156)Z75.92, P!0.001); Fig. 2A), sympathectomy did not significantly alter bradykinin-hyperalgesia in sound stressed rats (P!0.85). Since, sympathectomy failed to attenuate bradykininhyperalgesia in sound stressed animals, the possibility of increased levels of plasma epinephrine to induce sensitivity to bradykinin in primary afferents was explored. As shown in Fig. 2B, epinephrine implants restored bradykininhyperalgesia in unstressed sympathectomized rats. The groups responded differently to bradykinin (F(2,116)Z 15.93, P!0.001), but there was no significant difference in the hyperalgesic effect of bradykinin between sham stressed and epinephrine implanted groups (PZ0.84). 3.3. Latency to onset of bradykinin-hyperalgesia in sound stressed animals Whereas bradykinin-hyperalgesia has a delayed peak effect in the normal rat, that produced by the direct-acting hyperalgesic agent PGE2 is much more rapid (Khasar et al.,

Fig. 1. Dose-response curves for the effect of (A) bradykinin and (B) prostaglandin E2 (PGE2) sham and sound stressed male rats. Whereas bradykininhyperalgesia is significantly enhanced in sound stressed rats, PGE2 hyperalgesia is not significantly affected by sound stress.

82

S.G. Khasar et al. / Pain 116 (2005) 79–86

Fig. 2. (A) The enhancement of bradykinin-hyperalgesia by sound stress was not affected by lumbar sympathectomy (compare triangles and filled circles), suggesting a sympathetic-independent hyperalgesia. On the other hand, bradykinin-hyperalgesia was significantly attenuated in sham stressed rats. The effect of bradykinin in non-sympathectomized sound stressed rats (dotted line) is shown for ease of comparison. (B) Administration of epinephrine (via Alzetw pumps) for 7 days restored bradykinin-hyperalgesia in sympathectomized rats. Both here and in Fig. 4, the sham stress and sound stress data (dotted lines in A and B) are the same as data in Fig. 1, while the Sympx (sham stress) (data dotted line in B) are the same as in A. Sympx, sympathectomy.

2002; Taiwo et al., 1987). Since, bradykinin-hyperalgesia was no longer sympathetic-dependent after sound stress, we tested the hypothesis that bradykinin was acting directly on primary afferents to produce hyperalgesia in sound stressed rats by evaluating its latency to onset (Khasar et al., 2002; Taiwo and Levine, 1989; Taiwo et al., 1987) in the sound stressed rat. Bradykinin (1 mg) produced a much more rapid onset of hyperalgesia in sound stressed rats than in sham stressed controls (Fig. 3). At the first measurement of postbradykinin injection (1 min), its hyperalgesia had almost reached its peak effect in sound stressed rats, whereas in the sham group, the peak effect was reached between 10 and 20 min after injection. Analysis of the first 5 min showed that bradykinin-hyperalgesia in sound-stressed animals was significantly enhanced compared to controls (F(1,80)Z 193.99, P!0.001).

sound-stressed group (F(2,180)Z27.64, P!0.001), but not from each other (PZ0.99). Similarly, the adrenal denervated groups, whether sound stressed or not, were significantly different from the non-denervated, soundstressed group (F(2,196)Z42.28, P!0.001), but not from each other (PZ0.99). As shown previously (Khasar et al., 1998b, 2003c), removal of the adrenal medulla or its denervation increased the baseline nociceptive threshold,

3.4. Effect of adrenal medullectomy or denervation The adrenal medulla is the major source of plasma epinephrine and sound stress causes an increase in plasma epinephrine (Green and Levine, 2005). Therefore, we evaluated the contribution of the adrenal medulla to the enhancement of bradykinin-hyperalgesia by removing or denervating the adrenal medulla. Adrenal medullectomy or denervation reversed sound stress-induced enhancement of bradykinin-hyperalgesia (Fig. 4A and B). The adrenal medullectomized groups, whether sound stressed or not, were significantly different from the non-medullectomized,

Fig. 3. Latency to onset of bradykinin-hyperalgesia in sound stressed and sham stressed rats. Whereas the hyperalgesic effect of bradykinin was almost maximal at the first measurement (1 min after injection) in sound stressed group of rats, it was much slower in the sham group.

S.G. Khasar et al. / Pain 116 (2005) 79–86

83

Fig. 4. The enhancement of bradykinin-hyperalgesia in sound stressed rats is reversed by (A) adrenal medullectomy and (B) adrenal denervation, suggesting the involvement of the adrenal medullar in stress-induced enhancement of bradykinin-hyperalgesia. AMedx, adrenal medullectomy; AMdenerv, adrenal denervation.

which was not altered by sound stress ((AMedx-sham stress, 121.0G2.4 g (nZ12); AMedx-sound stress 119.7G2.2 g, PZ0.69 (nZ12); AMdenerv-sham stress 121.3G2.6 g (nZ16); AMdenerv-sound stress 119.4G2.3 g, PZ0.59 (nZ16)).

4. Discussion The results of this study show that repeated nonhabituating sound stress enhanced bradykinin-induced mechanical hyperalgesia and converted it from being postganglionic sympathetic neuron-dependent to being sympathetic-independent. Thus, unlike in sympathectomized, sham stressed control rats, bradykinin-hyperalgesia in sympathectomized, sound stressed rats was not attenuated. These effects of stress required activity in the sympathetic pre-ganglionic supply and function of the adrenal medulla, since denervation or removal of the adrenal medulla reversed the effect of sound stress. These observations suggest that adrenal medullary factors released during stress act in some way to increase the sensitivity of the primary afferent nociceptor to bradykinin. While more specific confirmatory experiments remain to be done, based on the rapid onset and sympathetic independence of bradykininhyperalgesia in sound stressed rats, we suggest a direct action of bradykinin on its primary afferent receptors. This hypothesized direct action of bradykinin on primary afferents, after repeated sound stress, represents

a fundamental change in the mechanism mediating the hyperalgesic action of bradykinin, which in normal rats, has been shown to require the presence of post-ganglionic sympathetic neurons (Khasar et al., 1998a, 2002; Levine et al., 1986; Taiwo et al., 1990). Whether stress-induced increase in sensitivity of primary afferents to bradykinin is at the receptor level, second messenger level or both, is still being investigated. However, it is doubtful that the increased sensitivity is due to induction of the B1 receptor subtype, since in vagotomy-induced enhancement of bradykinin-hyperalgesia, there is increased plasma epinephrine as well as sympathetic independence of bradykininhyperalgesia, but the B1 receptor subtype is not involved (Khasar et al., 2002, 2003b). It is noteworthy that whereas in control rats, the post-ganglionic sympathetic neurondependent hyperalgesic effect of bradykinin is mediated by PGE2 (Taiwo and Levine, 1988), PGE2 hyperalgesia, in the current study, is not affected by sound stress, further supporting the suggestion that in sound stressed rats, bradykinin-hyperalgesia is independent of PGE2 release from the post-ganglionic sympathetic neuron. It also demonstrates that stress differentially affects the hyperalgesia induced by inflammatory mediators, even when they act directly on primary afferent nociceptors. The lack of effect of sound stress on baseline mechanical nociceptive threshold, even in adrenal medullectomized or denervated animals, is consistent with the inability of increased plasma levels of epinephrine to alter baseline nociceptive threshold in male rats (Khasar et al., 2003b) and supports our earlier

84

S.G. Khasar et al. / Pain 116 (2005) 79–86

suggestion that modulation of baseline nociceptive threshold and bradykinin-hyperalgesia are mediated by different mechanisms (Khasar et al., 1998b, 2003b). As demonstrated in vagotomized rats or those that were directly implanted with epinephrine (Khasar et al., 1998b, 2003b), prolonged high levels of plasma epinephrine enhance bradykinin-hyperalgesia. The short latency to onset of bradykinin-hyperalgesia and its resistance to sympathectomy, in vagotomized rats (Khasar et al., 2002), suggest a direct action of bradykinin on primary afferents (Levine et al., 1986; Taiwo et al., 1987). In line with these observations, it has been demonstrated in the current study (using implants of epinephrine), that increased plasma levels of epinephrine can restore bradykinin-hyperalgesia in sympathectomized animals. Thus, our observation that in animals subjected to repeated sound stress, resulting in increased levels of plasma epinephrine (Green and Levine, 2005), bradykinin-hyperalgesia is no longer dependent on post-ganglionic sympathetic neurons, agrees with results of previous studies, which found that in vagotomized rats, bradykinin-hyperalgesia has a sympathetic-independent component (Khasar et al., 2002). Of note, our results are in general agreement with the findings of other researchers, that chronic stress is pronociceptive (da Silva Torres et al., 2003a,b; Jorum, 1988c; Vidal and Jacob, 1982, 1986), even though different forms of stress as well as different methods of assessing hyperalgesia were employed (Ashkinazi and Vershinina, 2000; da Silva Torres et al., 2003b; Jorum, 1988a; Vidal and Jacob, 1982, 1986). Stress-induced hyperalgesia has been suggested to be due to a deficiency in central dopaminergic systems (Wood, 2004). However, whether stress-induced increase in plasma epinephrine level is a consequence of dopamine depletion or in spite of it, is not known. Since, our studies demonstrate that removal or denervation of the adrenal medulla can account for, at least, sound stress-induced enhancement of mechanical hyperalgesia, any contribution of a central dopaminergic mechanism may be mediated through the adrenal medulla. The proposed neural circuitry of sound stress-induced enhancement of bradykinin-hyperalgesia is shown in Fig. 5. An important aspect of this study is the link between repeated non-habituating sound stress, enhancement of bradykinin-induced mechanical hyperalgesia, and adrenal medullary function. The adrenal medulla is a major effector organ in stress and main source of epinephrine in the peripheral circulation. Stress is known to exacerbate symptoms in patients with generalized chronic pain syndromes, such as of fibromyalgia and irritable bowel syndrome (Cleare, 2004; Davis et al., 2001; Herrmann et al., 2000; Hudson et al., 2003). Although mechanisms mediating generalized pain syndromes are still unclear, our results are in agreement with the hypothesis that chronic or repeated stress may attenuate the hypothalamopituitary adrenal axis feedback mechanism, which is

Sound stress PVN Brainstem

CRH

LC

Adrenal cortex medulla 1

2

Sympathetic outflow

Epinephrine

Spinal cord

1 Removal of the adrenal medulla 2 Adrenal medulla denervation

Nociceptive afferents Skin

Fig. 5. Schematic diagram of proposed circuit for stress-induced enhancement of BK mechanical hyperalgesia. Stressful stimuli from higher centers activate the paraventricular nucleus (PVN), stimulating the production of corticotropin-releasing hormone (CRH), a coordinator of the stress response (Black and Garbutt, 2002). Activation of the locus coeruleus (LC) by CRH is transmitted to the adrenal medulla via sympathetic fibers in the splanchnic nerve, leading to the release of epinephrine (Black and Garbutt, 2002).

anti-inflammatory in acute stress (Blackburn-Munro and Blackburn-Munro, 2001). The result is the progression of inflammatory process, with the release of more inflammatory mediators that sensitize nociceptors (Black, 2002, 2003; Black and Garbutt, 2002; Blackburn-Munro and Blackburn-Munro, 2001). Thus, our observations have the potential to shed more light on the possible mechanisms of such generalized chronic pain syndromes. Pursuit of the mechanism by which bradykinin produces hyperalgesia by the hypothesized direct action on primary afferent nociceptors and the phenotypic switch leading to the ability of primary afferent nociceptors to develop this sensitivity to bradykinin are currently being investigated. In conclusion, we have demonstrated that repeated, nonhabituating sound stress enhances bradykinin mechanical hyperalgesia, and makes it post-ganglionic sympathetic neuron-independent, an effect produced by chronic elevation of plasma levels of adrenal medulla-derived epinephrine. The contribution of other factors, central or peripheral, is not excluded.

S.G. Khasar et al. / Pain 116 (2005) 79–86

Acknowledgements We thank Mr Dennis Mendoza for technical assistance. This study was funded by NIH grant no. AR 048821.

References Adler GK, Manfredsdottir VF, Creskoff KW. Neuroendocrine abnormalities in fibromyalgia. Curr Pain Headache Rep 2002;6:289–98. Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology 1997;49:52–7. Aley KO, McCarter G, Levine JD. Nitric oxide signaling in pain and nociceptor sensitization in the rat. J Neurosci 1998;18:7008–14. Aley KO, Messing RO, Mochly-Rosen D, Levine JD. Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci 2000;20:4680–5. Araki T, Ito K, Kurosawa M, Sato A. Responses of adrenal sympathetic nerve activity and catecholamine secretion to cutaneous stimulation in anesthetized rats. Neuroscience 1984;12:289–99. Ashkinazi I, Vershinina EA. Nociceptive system response to repetitive painful stimuli during chronic psychoemotional stress in humans. Ross Fiziol Zh Im I M Sechenova 2000;86:1441–8. Baron R, Ja¨nig W. Sympathetic and afferent neurons projecting in the splenic nerve of the cat. Neurosci Lett 1988;94:109–13. Baron R, Ja¨nig W, Kollmann W. Sympathetic and afferent somata projecting in hindlimb nerves and the anatomical organization of the lumbar sympathetic nervous system of the rat. J Comp Neurol 1988; 275:460–8. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 2002;16:622–53. Black PH. The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 2003;17: 350–64. Black PH, Garbutt LD. Stress, inflammation and cardiovascular disease. J Psychosom Res 2002;52:1–23. Blackburn-Munro G, Blackburn-Munro RE. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol 2001; 13:1009–23. Bradley LA, McKendree-Smith NL. Central nervous system mechanisms of pain in fibromyalgia and other musculoskeletal disorders: behavioral and psychologic treatment approaches. Curr Opin Rheumatol 2002;14: 45–51. Bradley LA, McKendree-Smith NL, Alarcon GS, Cianfrini LR. Is fibromyalgia a neurologic disease? Curr Pain Headache Rep 2002;6: 106–14. Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 2000;12:113–23. Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 2001;13:117–27. Celler BG, Schramm LP. Pre- and postganglionic sympathetic activity in splanchnic nerves of rats. Am J Physiol 1981;241:R55–61. Cleare AJ. Stress and fibromyalgia—what is the link? J Psychosom Res 2004;57:423–5. Cohen H, Neumann L, Shore M, Amir M, Cassuto Y, Buskila D. Autonomic dysfunction in patients with fibromyalgia: application of power spectral analysis of heart rate variability. Semin Arthritis Rheum 2000;29:217–27. da Silva Torres IL, Bonan CD, Crema L, De Leon Nunes M, Battastini AM, Sarkis JJ, Dalmaz C, Ferreira MB. Effect of drugs active at adenosine receptors upon chronic stress-induced hyperalgesia in rats. Eur J Pharmacol 2003a;481:197–201.

85

da Silva Torres IL, Cucco SN, Bassani M, Duarte MS, Silveira PP, Vasconcellos AP, Tabajara AS, Dantas G, Fontella FU, Dalmaz C, Ferreira MB. Long-lasting delayed hyperalgesia after chronic restraint stress in rats-effect of morphine administration. Neurosci Res 2003b;45: 277–83. Davis MC, Zautra AJ, Reich JW. Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med 2001;23:215–26. Dina OA, Barletta J, Chen X, Mutero A, Martin A, Messing RO, Levine JD. Key role for the epsilon isoform of protein kinase C in painful alcoholic neuropathy in the rat. J Neurosci 2000;20:8614–9. Dina OA, McCarter GC, de Coupade C, Levine JD. Role of the sensory neuron cytoskeleton in second messenger signaling for inflammatory pain. Neuron 2003;39:613–24. Green PG, Levine JD. Sexual dimorphism in the effect of non-habituating stress on neurogenic plasma extravasation. Eur J Neurosci 2005;3872: 1–7. Herrmann M, Scholmerich J, Straub RH. Stress and rheumatic diseases. Rheum Dis Clin North Am 2000;26:737–63, viii. Hudson JI, Mangweth B, Pope Jr HG, De Col C, Hausmann A, Gutweniger S, Laird NM, Biebl W, Tsuang MT. Family study of affective spectrum disorder. Arch Gen Psychiatry 2003;60:170–7. Jorum E. Analgesia or hyperalgesia following stress correlates with emotional behavior in rats. Pain 1988a;32:341–8. Jorum E. Noradrenergic mechanisms in mediation of stress-induced hyperalgesia in rats. Pain 1988b;32:349–55. Jorum E. Noradrenergic mechanisms in mediation of stress-induced hyperalgesia in rats [published erratum appears in Pain 1988 Sep;34(3):322. Pain 1988c;32:349–55. Joseph EK, Parada CA, Levine JD. Hyperalgesic priming in the rat demonstrates marked sexual dimorphism. Pain 2003;105:143–50. Khasar SG, Miao FJ-P, Ja¨nig W, Levine JD. Modulation of bradykinininduced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents. Eur J Neurosci 1998a;10:435–44. Khasar SG, Miao FJ-P, Ja¨nig W, Levine JD. Vagotomy-induced enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated. J Neurosci 1998b;18:3043–9. Khasar SG, McCarter G, Levine JD. Epinephrine produces a betaadrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. J Neurophysiol 1999;81:1104–12. Khasar SG, Miao FJ-P, Gear RW, Green PG, Isenberg WM, Levine JD. Sympathetic-independent bradykinin mechanical hyperalgesia induced by subdiaphragmatic vagotomy in the rat. J Pain 2002;3:369–76. Khasar SG, Green PG, Gear RW, Isenberg W, Levine JD. Gonadal hormones do not account for sexual dimorphism in vagal modulation of nociception in the rat. J Pain 2003a;4:190–6. Khasar SG, Green PG, Miao FJ, Levine JD. Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat. Eur J Neurosci 2003b;17:909–15. Khasar SG, Miao FJ, Gear RW, Green PG, Levine JD. Vagal modulation of bradykinin-induced mechanical hyperalgesia in the female rat. J Pain 2003c;4:278–83. Lembeck F, Popper H, Juan H. Release of prostaglandins by bradykinin as an intrinsic mechanism of its algesic effect. Naunyn Schmiedebergs Arch Pharmacol 1976;294:69–73. Levine JD, Taiwo YO, Collins SD, Tam JK. Noradrenaline hyperalgesia is mediated through interaction with sympathetic postganglionic neurone terminals rather than activation of primary afferent nociceptors. Nature 1986;323:158–60. Miao FJ, Benowitz NL, Basbaum AI, Levine JD. Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinininduced plasma extravasation in the knee joint of the rat. J Pharmacol Exp Ther 1992;262:889–95. Mousa S, Miller Jr CH, Couri D. Corticosteroid modulation and stressinduced analgesia in rats. Neuroendocrinology 1981;33:317–9.

86

S.G. Khasar et al. / Pain 116 (2005) 79–86

Naranjo A, Ojeda S, Francisco F, Erausquin C, Rua-Figueroa I, RodriguezLozano C. Fibromyalgia in patients with rheumatoid arthritis is associated with higher scores of disability. Ann Rheum Dis 2002;61: 660–1. Pacak K, Palkovits M. Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 2001; 22:502–48. Pacak K, Palkovits M, Kopin IJ, Goldstein DS. Stress-induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary–adrenocortical and sympathoadrenal activity: in vivo microdialysis studies. Front Neuroendocrinol 1995;16:89–150. Racotta R, Ramirez-Altamirano L, Velasco-Delgado E. Metabolic effects of chronic infusions of epinephrine and norepinephrine in rats. Am J Physiol 1986;250:E518–22. Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep 2002;6: 259–66. Strausbaugh HJ, Green PG, Dallman MF, Levine JD. Repeated, nonhabituating stress suppresses inflammatory plasma extravasation by a novel, sympathoadrenal dependent mechanism. Eur J Neurosci 2003; 17:805–12. Taiwo YO, Levine JD. Characterization of the arachidonic acid metabolites mediating bradykinin and noradrenaline hyperalgesia. Brain Res 1988; 458:402–6. Taiwo YO, Levine JD. Prostaglandin effects after elimination of indirect hyperalgesic mechanisms in the skin of the rat. Brain Res 1989;492: 397–9. Taiwo YO, Goetzl EJ, Levine JD. Hyperalgesia onset latency suggests a hierarchy of action. Brain Res 1987;423:333–7. Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD. Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience 1989a;32:577–80.

Taiwo YO, Coderre TJ, Levine JD. The contribution of training to sensitivity in the nociceptive paw-withdrawal test. Brain Res 1989b; 487:148–51. Taiwo YO, Heller PH, Levine JD. Characterization of distinct phospholipases mediating bradykinin and noradrenaline hyperalgesia. Neuroscience 1990;39:523–31. Triadafilopoulos G, Simms RW, Goldenberg DL. Bowel dysfunction in fibromyalgia syndrome. Dig Dis Sci 1991;36:59–64. Vidal C, Jacob J. Hyperalgesia induced by non-noxious stress in the rat. Neurosci Lett 1982;32:75–80. Vidal C, Jacob J. Hyperalgesia induced by emotional stress in the rat: an experimental animal model of human anxiogenic hyperalgesia. Ann N Y Acad Sci 1986;467:73–81. Waylonis GW, Heck W. Fibromyalgia syndrome. New associations. Am J Phys Med Rehabil 1992;71:343–8. Widy-Tyszkiewicz E, Mierzejewski P, Kohutnicka M, Czlonkowski A. Cold water stress induced analgesia in unilateral inflammation of the hindpaw in hypertensive and normotensive rats. Pol J Pharmacol 1995; 47:313–20. Wilkinson CW, Shinsako J, Dallman MF. Return of pituitary–adrenal function after adrenal enucleation or transplantation: diurnal rhythms and responses to ether. Endocrinology 1981;109:162–9. Willer JC, Dehen H, Cambier J. Stress-induced analgesia in humans: endogenous opioids and naloxone-reversible depression of pain reflexes. Science 1981;212:689–91. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. J Rheumatol 2004;31:695–700. Wood PB. Stress and dopamine: implications for the pathophysiology of chronic widespread pain. Med Hypotheses 2004;62:420–4. Yunus MB. Gender differences in fibromyalgia and other related syndromes. J Gend Specif Med 2002;5:42–7.