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Dynorphin Promotes Abnormal Pain and Spinal Opioid Antinociceptive Tolerance

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Dynorphin Promotes Abnormal Pain and Spinal Opioid Antinociceptive Tolerance The Journal of Neuroscience, September 15, 2000, 20(18):7074–7079 Dynorphin Promotes Abnormal Pain and Spinal Opioid Antinociceptive Tolerance Todd W. Vanderah, Luis R. Gardell, Shannon E. Burgess, Mohab Ibrahim, Ahmet Dogrul, Cheng-Min Zhong, En-Tan Zhang, T. Philip Malan Jr, Michael H. Ossipov, Josephine Lai, and Frank Porreca Departments of Pharmacology and Anesthesiology, University of Arizona, Tucson, Arizona 85724 The nonopioid actions of spinal dynorphin may promote aspects allodynia and reversed thermal hyperalgesia to above baseline of abnormal pain after nerve injury. Mechanistic similarities have levels (i.e., antinociception). Spinal dynorphin antiserum, but not been suggested between opioid tolerance and neuropathic pain. control serum, also reestablished the antinociceptive potency Here, the hypothesis that spinal dynorphin might mediate effects and efficacy of spinal morphine. Neither dynorphin antiserum nor of sustained spinal opioids was explored. Possible abnormal control serum administration altered baseline non-noxious or pain and spinal antinociceptive tolerance were evaluated after noxious thresholds or affected the intrathecal morphine antino- 2 4 5 intrathecal administration of [D-Ala , N-Me-Phe , Gly-ol ]enke ciceptive response in saline-infused rats. These data suggest phalin (DAMGO), an opioid ␮ agonist. Rats infused with DAMGO, that spinal dynorphin promotes abnormal pain and acts to re- but not saline, demonstrated tactile allodynia and thermal hyper- duce the antinociceptive efficacy of spinal opioids (i.e., toler- algesia of the hindpaws (during the DAMGO infusion) and a ance). The data also identify a possible mechanism for previously decrease in antinociceptive potency and efficacy of spinal opi- unexplained clinical observations and offer a novel approach for oids (tolerance), signs also characteristic of nerve injury. Spinal the development of strategies that could improve the long-term DAMGO elicited an increase in lumbar dynorphin content and a use of opioids for pain. decrease in the ␮ receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal Key words: dynorphin; abnormal pain; morphine tolerance; administration of dynorphin A(1–17) antiserum blocked tactile spinal; dynorphin antiserum; ␮-opioid receptors An important clinical observation is that sustained spinal admin- the NMDA receptor activation during chronic opioid exposure is istration of ␮-opioids produces abnormal pain that is reminiscent uncertain. NMDA receptors may coexist on cells expressing opioid of neuropathic pain (Woolf, 1981; Ali, 1986; Arner et al., 1988; receptors, including primary afferent fibers (Liu et al., 1994, 1997). Yaksh and Harty, 1988; De Conno et al., 1991; Trujillo and Akil, Primary afferent neurons do not tend to discharge spontaneously 1991; Devulder, 1997). Paradoxical opioid-induced novel pain of- and are probably not essential to the development of opioid toler- ten occurs in areas isolated from the site of the original pain ance (Price, 1988), suggesting the importance of intracellular path- complaint (De Conno et al., 1991). Additionally, decreased anal- ways as a potential mechanism by which NMDA antagonists might gesia after sustained spinal ␮-opioids is similar to the diminished affect tolerance. Another possibility may be that an intermediary effects of spinal ␮-opioids in animal models of neuropathy. Thus, might mechanistically link opioid tolerance and nerve injury di- both opioid tolerance and neuropathic conditions share features of rectly or indirectly via the NMDA receptor. diminished ␮-opioid analgesia with abnormal pain (thermal hyper- A feature of both nerve-injury pain and opioid treatment is algesia and tactile allodynia). These common features have led to increased spinal dynorphin (Cho and Basbaum, 1989; Kajander et suggestions of common mechanisms in nerve-injury and in spinal al., 1990; Draisci et al., 1991; Dubner, 1991; Dubner and Ruda, ␮-opioid tolerance states (Mao et al., 1994, 1995a,b). 1992; Rattan and Tejwani, 1997). Dynorphin might be pronocicep- A similarity linking abnormal pain from opioids or nerve injury tive in chronic pain states (Bian et al., 1999; Malan et al., 2000). is the sensitivity to NMDA antagonists. NMDA antagonists re- Possible pronociceptive actions by spinal dynorphin are supported verse thermal hyperalgesia after nerve injury (Mao et al., 1995a,b; because dynorphin antiserum, but not control serum, (1) blocks Wegert et al., 1997; Bian et al., 1999). Additionally, the loss of nerve-injury hyperalgesia (Wegert et al., 1997), (2) restores spinal morphine antinociception in rats with spinal nerve injury was morphine antinociception after nerve injury (Nichols et al., 1997; restored by intrathecal MK-801, an NMDA antagonist (Ossipov et Wegert et al., 1997), (3) elicits spinal morphine antiallodynia, and al., 1995a,b). Similarly, tolerance and hyperalgesia produced by (4) restores the expected synergy of spinal/supraspinal morphine spinal injections and/or infusions of morphine were prevented by that is lost after nerve injury (Bian et al., 1999). The effects of MK-801 (Mao et al., 1994) or dextromethorphan (Trujillo and dynorphin A(1–17) antiserum parallel those seen with MK-801 and Akil, 1991; Tiseo and Inturrisi, 1993; Mao et al., 1994; Tiseo et al., suggest that dynorphin may interact, directly or indirectly, with the 1994; Manning et al., 1996); MK-801 did not produce antinocicep- NMDA receptor (Wegert et al., 1997; Bian et al., 1999; Tang et al., tion alone and did not increase morphine antinociception in non- 1999). tolerant rats. Here, the hypothesis that abnormal pain and decreased spinal Although the blockade of nerve-injury pain by NMDA antago- opioid antinociception seen after sustained opioid exposure might nists may be caused by the blockade of afferent discharge from be mediated by spinal dynorphin was tested. injured nerves, the mechanism by which NMDA antagonists block or reverse opioid tolerance is not understood because the source of MATERIALS AND METHODS Male Sprague Dawley rats (Harlan Sprague Dawley, Indianapolis, IN), 200–300 gm at the time of testing, were maintained in a climate-controlled Received March 29, 2000; revised June 30, 2000; accepted June 30, 2000. room on a 12 hr light/dark cycle (lights on at 06:00 A.M.) with food and Correspondence should be addressed to Dr. Frank Porreca, Department of Phar- water available ad libitum. All of the testing was performed in accordance macology, College of Medicine, University of Arizona Health Sciences Center, with the policies and recommendations of the International Association for Tucson, AZ 85724. E-mail: [email protected]. the Study of Pain and the National Institutes of Health guidelines for the Copyright © 2000 Society for Neuroscience 0270-6474/00/200001-06$15.00/0 handling and use of laboratory animals and received approval from the Vanderah et al. • Spinal Dynorphin Promotes Pain and Tolerance J. Neurosci., September 15, 2000, 20(18):7074–7079 7075 Animal Care and Use Committee of the University of Arizona. Groups of 5–10 rats were used in all experiments. Cannulation and drug administration. While under halothane anesthesia, all of the rats were implanted with intrathecal catheters (polyethylene-10 tubing; 7.5 cm) as described previously (Yaksh and Rudy, 1976) for drug administration at the level of the lumbar spinal cord. Chronic spinal infusions were performed with osmotic minipumps (Alza, Mountain View, 2 ␮ D CA). The osmotic pumps delivered saline at 1 l/hror[Ϫ Ϫ-Ala , N-Me- Phe 4, Gly-ol 5]enkephalin (DAMGO) at 1 nmol ⅐ ␮l 1 ⅐ hr 1 for7d.The minipumps were attached to the indwelling intrathecal catheters and placed in the subcutaneous space. On day 6 all animals were tested for tactile allodynia and thermal hyperalgesia while the infusions continued. On day 7 the minipumps were disconnected from the infusion catheter while the animals were briefly anesthetized with halothane and the infu- sion catheter was exteriorized. Morphine, control serum, or antiserum to dynorphin A(1–17) (200 ␮g per injection) was injected through the intra- thecal catheter in a volume of 5 ␮l followed by a 9 ␮l saline flush. Nociceptive/allodynic testing. Paw withdrawal thresholds were determined in response to probing with von Frey filaments in a range normally not found to be noxious (i.e., 0.40, 0.70, 1.20, 2.00, 3.63, 5.50, 8.50, and 15.1 gm). Each filament was applied perpendicularly to the plantar surface of the right paw of rats kept in suspended wire-mesh cages. The paw with- drawal threshold was determined by sequentially increasing and decreasing Figure 1. Left, Male Sprague DawleyϪ rats receivedϪ an intrathecal infusion the stimulus strength (“up-and-down” method) and analyzed with a Dixon of saline or of DAMGO (1 nmol ⅐ ␮l 1 ⅐ hr 1) for 7 d. The spinal cords nonparametric test (Dixon, 1980; Chaplan et al., 1994). Tactile allodynia Յ were removed and assayed for dynorphin content with an enzyme immu- was indicated by a significant ( p 0.05; Student’s t test) reduction in the noassay. The rats with DAMGO infusions showed a significant (*p Յ 0.05; paw withdrawal threshold when compared with that obtained before any Student’s t test) increase in spinal dynorphin content when compared with manipulations. Tactile allodynia was measured on day 6 of DAMGO saline-infused rats. Right, Antinociceptive tolerance on day 8 to intrathecal infusion while the DAMGO infusion was maintained. DAMGO (1 ␮g/5 ␮l; n ϭ 8; top) or cross-tolerance to intrathecal
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