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Interaction Between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain Dorien H

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Interaction Between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain Dorien H Anesthesiology 2003; 99:449–54 © 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Interaction between the Spinal Melanocortin and Opioid Systems in a Rat Model of Neuropathic Pain Dorien H. Vrinten, M.D., Ph.D.,* Willem Hendrik Gispen, Ph.D.,† Cor J. Kalkman, M.D., Ph.D.,‡ Roger A. H. Adan, Ph.D.§ Background: The authors recently demonstrated that admin- substance P, calcitonin gene–related peptide, cholecys- istration of the melanocortin-4 receptor antagonist SHU9119 tokinin, and neuropeptide Y.6,7 We recently demon- decreased neuropathic pain symptoms in rats with a sciatic strated that such plasticity also occurs in the spinal chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the melanocortin system, as demonstrated by an up-regula- spinal melanocortin system and tonic antinociceptive effects of tion of melanocortin-4 (MC4) receptors in the spinal cord the spinal opioid system. Therefore, they investigated a possi- dorsal horn in a rat model for neuropathic pain, the Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/99/2/449/407606/0000542-200308000-00028.pdf by guest on 25 September 2021 ble interaction between these two systems and tested whether chronic constriction injury (CCI).8,9 Because melano- opioid effectiveness could be increased through modulation of cortins have been shown to induce hyperalgesia,10,11 the spinal melanocortin system activity. Methods: In chronic constriction injury rats, melanocortin this increase in spinal MC4 receptors might contribute to and opioid receptor ligands were administered through a lum- the increased sensitivity in neuropathic pain, through bar spinal catheter, and their effects on mechanical allodynia activation by the endogenous melanocortin receptor ag- were assessed by von Frey probing. onist ␣-melanocyte–stimulating hormone (␣-MSH), ␮ Results: Naloxone (10–100 g) dose-dependently increased which is also known to be present in the dorsal horn.12 ,(allodynia (percent of maximum possible effect of ؊67 ؎ 9% which is in agreement with a tonic antinociceptive effect of the An interaction between the central melanocortin and opioid system. SHU9119 decreased allodynia (percent of maxi- opioid system has been described previously. Melanocort- mum possible effect of 60 ؎ 13%), and this effect could be ins can reduce morphine-induced analgesia13,14 inhibit the blocked by a low dose of naloxone (0.1 ␮g), which by itself had development of opioid tolerance,13,15 counteract opioid ␮ no effect on withdrawal thresholds. Morphine (1–10 g) dose- addiction,16 and induce morphine withdrawal–like symp- dependently decreased allodynia (percent of maximum possi- 17 -ble effect of 73 ؎ 14% with the highest dose tested). When toms. However, it is not known whether such a func ␮g SHU9119 (percent of maximum possible effect of 47 ؎ tional antagonism between the melanocortin and opioid 0.5 14%) was given 15 min before morphine, there was an additive system also exists at the spinal level. antiallodynic effect of both compounds. It is generally accepted that in neuropathic pain, opi- Conclusions: Together, these data confirm that there is an oids are less effective. To obtain adequate pain relief, interaction between the spinal melanocortin and opioid sys- 18 tems and that combined treatment with melanocortin-4 recep- high doses of opioids are needed ; thus, their use is tor antagonists and opioids might possibly contribute to the often limited by unwanted side effects. Possible expla- treatment of neuropathic pain. nations for this right shift in the dose–response curve of opioids include a loss of opioid receptors on primary NEUROPATHIC pain is characterized by allodynia (pain afferent terminals after axotomy19,20 and an increased due to a normally nonpainful stimulus) and hyperalgesia activity of endogenous antiopioids such as dynorphin21 (increased pain in response to a normally painful stimu- or cholecystokinin22,23 in the spinal cord. Considering lus). It has become clear that numerous pathophysio- the functional antagonism between the melanocortin logic changes in response to neuronal or axonal damage and opioid system, it is possible that the aforementioned contribute to neuropathic pain.1,2 Not only do neuro- changes in the spinal melanocortin system in neuro- atomical changes occur, such as loss of axotomized pri- pathic pain9 might also contribute to the reduced anal- mary afferent fibers,3 apoptotic cell loss,4 and reorgani- gesic effect of morphine in this condition. zation of dorsal horn circuitry,5 but also the expression We therefore investigated a possible interaction be- of different neurotransmitters and their receptors in sen- tween melanocortin and opioid systems at the spinal sory neurons is altered. Such plasticity has been de- level by administering different combinations of the opi- scribed in a number of messenger systems, including oid receptor antagonist naloxone and agonist morphine, and the MC4 receptor antagonist SHU9119 and agonist MTII. We hypothesized that through modulation of the * Resident in Anesthesiology, Departments of Medical Pharmacology and An- esthesiology, † Professor of Neurosciences, § Professor of Molecular Pharmacol- activity of the spinal melanocortin system, it is possible ogy, Department of Medical Pharmacology, ‡ Professor of Anesthesiology, De- to increase the effectiveness of opioids in neuropathic partment of Anesthesiology. pain. Received from the Department of Medical Pharmacology and Anesthesiology, Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands. Submitted for publication September 20, 2002. Accepted for publication March 19, 2003. Support was provided solely from institutional and/or departmental sources. Materials and Methods Address reprint requests to Dr. Vrinten: Rudolf Magnus Institute for Neuro- sciences, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Animals Utrecht, The Netherlands. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the Journal Web site, Thirty male Wistar rats weighing 250–300 g at the start www.anesthesiology.org. of the study were used. Animals were housed in groups Anesthesiology, V 99, No 2, Aug 2003 449 450 VRINTEN ET AL. of two or three in plastic cages on sawdust bedding. first drug was given 15 min before the second drug, They were kept at a 12/12-h light/dark cycle, with food because we previously demonstrated that the peak ef- and water available ad libitum. All testing procedures in fect of SHU9119 is at 15 min after injection.9 this study were performed according to the Ethical On a typical testing day, all 27 animals were randomly Guidelines of the International Association for the Study divided into three groups (n ϭ 8 or 9 each, except for of Pain24 and approved of by the Ethics Committee on simultaneous administration of MTII and morphine, Animal Experiments of Utrecht University (Utrecht, The where n ϭ 4). Each group randomly received one treat- Netherlands). ment, with the experimenter blinded to the allocation. Thereafter, animals were given at least 2 days of rest to Surgery minimize any possibility of drug interactions or develop- Animals were anesthetized with a single intramuscular ment of tolerance.9 On the next testing day, all animals Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/99/2/449/407606/0000542-200308000-00028.pdf by guest on 25 September 2021 injection of Hypnorm (Janssen Pharmaceutical Ltd., were again randomly divided into three groups, and Grove, Oxford) containing 0.315 mg/ml fentanyl citrate three other treatments were given. This design was con- and 10 mg/ml fluanisone, at a dose of 1 ml/kg body tinued until all treatments had been given to one group weight. of animals. Thus, in total, 18 groups were tested, and Four ligatures were placed around the right sciatic therefore, each animal was used multiple times on con- nerve as previously described by Bennett and Xie,8 and secutive testing days. the incision was closed with silk sutures. Two weeks after the CCI lesion, rats were anesthetized with a mix- Mechanical Stimulation Test ture of oxygen–nitrous oxide (1:2) and 2.5% halothane. Foot withdrawal threshold in response to a mechanical A lumbar spinal catheter was placed as described by stimulus was determined using a series of von Frey Storkson et al.25 and subcutaneously tunneled to the filaments (Stoelting, Wood Dale, IL), ranging from 1.08 neck region. After recovery from anesthesia and also at to 21.09 g. Animals were placed in a plastic cage with a the end of all experiments, proper placement of the metal mesh floor, allowing them to move freely. They catheters was checked by injecting 15 ␮l of lidocaine, were allowed to acclimatize to this environment before 2%, which gives an immediate and short-lasting motor the experiment. The filaments were presented to the paralysis of the hind limbs on intraspinal injection. Be- midplantar surface as described by Chaplan et al.,27 and cause of incorrect placement of the spinal catheter, 3 the smallest filament eliciting a foot withdrawal response rats were excluded from this study, thus leaving a total of was considered the threshold stimulus. 27 animals. They were allowed to recover before testing Baseline values were determined, and measurements was initiated. were repeated 60 min after drug or vehicle administra- tion (in case of a pretreatment, measurements were Drugs
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