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Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord Carolyn A

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Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord Carolyn A Ⅵ PAIN MEDICINE Anesthesiology 2009; 110:638–47 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Clonidine and Dexmedetomidine Produce Antinociceptive Synergy in Mouse Spinal Cord Carolyn A. Fairbanks, Ph.D.,* Kelley F. Kitto,† H. Oanh Nguyen, B.S.,‡ Laura S. Stone, Ph.D.,§ George L. Wilcox, Ph.D.࿣ Background: Synergy between drugs manifests with in- disparate anatomical sites or distinct receptors coresid- creased potency and/or efficacy of the combination relative to ing at a common anatomical location. Examples of well- either agonist given alone. Synergy is typically observed be- tween drugs of different classes, as is the case with the ␣-adren- described synergistic agonist pairs include selective ago- ergic–opioid receptor synergy often observed in preclinical nists of the ␮- and ␦-opioid receptor subtypes as well as Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/3/638/368471/0000542-200903000-00032.pdf by guest on 26 September 2021 studies. However, rare studies report synergy between agonists either of those subtypes combined with agonists target- of the same class. The current study examined the analgesic ␣ ing the 2-adrenergic receptors (ARs). interaction between two intrathecally injected ␣ -adrenergic 2 The analgesic and anesthetic properties of ␣ AR-selec- receptor (AR) agonists previously thought to act at the same 2 receptor subtype when given spinally. tive agonists have been known for decades. Develop- Methods: Mice were given clonidine, dexmedetomidine, or ment of clinical applications of these agonists remains an the combination spinally to evaluate the interaction between area of interest, particularly as adjuvants for pain man- 1 these two agonists. The ED50 values were calculated, and the agement and as anesthetic-sparing agents. In contrast to interactions were tested by isobolographic analysis. The ro- the opioid receptor–selective agonists, definition of the tarod test was performed in the same mice after the completion ␣ of analgesic assessment to assess motor or sedative effects. pharmacologic profile of each 2AR agonist has been These experiments were performed in outbred mice as well as limited because of poor ligand selectivity across the ␣ ␣ ␣ ␣ ␣ ␣ 2 in mice with mutant 2AARs, 2CAR knockout mice, or wild-type three 2AR subtypes: 2AAR, 2BAR, and 2CAR. The controls. Finally, analgesic cross-tolerance between clonidine ␣ 2AR subtypes are differentially expressed in specific and dexmedetomidine was evaluated. regions of the central nervous system. For example, in Results: Clonidine and dexmedetomidine interacted syner- ␣ the spinal cord, ␣ ARs seem to be principally of pri- gistically in all lines except the 2CAR knockout line, implicat- 2A ␣ ␣ ing 2CARs in the interaction. In addition, clonidine and dexme- mary afferent neuron origin, whereas 2CARs seem to be detomidine did not show analgesic cross-tolerance in the expressed primarily on neurons intrinsic to the spinal outbred strain, suggesting that the two drugs have distinct cord.3 The evidence for ␣ AR expression in spinal cord mechanisms of action. 2B Conclusions: The current study introduces a new synergistic nerve terminals and intrinsic spinal neurons is not con- ␣ 4,5 ␣ 6 agonist pair, clonidine–dexmedetomidine. These two drugs clusive. Activation of both 2AARs and 2CARs has ␣ seem to require the 2AAR for spinal analgesia when given been reported to result in antinociception. Therefore, it separately; when delivered as a combination, the resultant syn- is reasonable to propose that concurrent participation of ␣ ergistic interaction requires the 2CAR as well. ␣ ␣ 2AARs and 2CARs could result in analgesic synergy. ␣ 4,5 Support for a positive interaction between 2AARs and SYNERGISTIC drug interactions result in enhanced po- ␣ 2CARs is provided in a previous report that evaluated tency and/or efficacy when one agent is given together ␣ 7 interactions between two 2-adrenergic agonists that with another. Therapeutic application of synergistic ␣ were thought to act at different 2AR subtypes based on combinations carries the expectation of efficacy at re- differences in the pharmacology of their antagonist sen- duced doses and, theoretically, reduced side effects. sitivity. To approach this question systematically, we Although the mechanisms underlying synergistic inter- ␣ have initiated a broad evaluation of several 2AR agonist actions are not well understood, synergy is thought to ␣ ␣ combinations in mouse lines deficient in 2AAR or 2CAR result from simultaneous action of the two agents at two function. As part of this larger program, the current distinct sites, such as a common receptor located at study evaluated the interaction between intrathecally administered clonidine and dexmedetomidine. Previous * Associate Professor, † Assistant Scientist, ‡ Research Coordinator, Depart- ␣ studies of 2AAR mutant mice have been interpreted to ments of Pharmaceutics, Pharmacology, and Neuroscience, ࿣ Professor, Depart- ments of Neuroscience, Pharmacology, and Dermatology, University of Minne- indicate that the potency and/or efficacy of both of these sota. § Assistant Professor, Alan Edwards Centre for Research on Pain and ␣ agonists is primarily dependent on 2AAR activation, Department of Pharmacology, McGill University, Montreal, Quebec, Canada. particularly when administered intrathecally. Because of Received from the Departments of Pharmaceutics, Pharmacology, and Neuro- science, University of Minnesota, Minneapolis, Minnesota. Submitted for publi- this prevailing view, we did not expect that coadminis- cation April 9, 2008. Accepted for publication August 19, 2008. Supported by tration of clonidine with dexmedetomidine would result grant Nos. R01-DA-15438 (Dr. Wilcox) and K01-DA-00509 to (Dr. Fairbanks) from the National Institute on Drug Abuse, Bethesda, Maryland. Zeneca Pharmaceuti- in a synergistic analgesic interaction. Our observations cals, Wilmington, Delaware, provided dexmedetomidine. indicate, however, that this combination produces de- Address correspondence to Dr. Fairbanks: Department of Pharmaceutics, finitive and replicable synergistic analgesia in several 9-177 Weaver Densford Hall, 308 Harvard Street Southeast, Minneapolis, Minne- sota 55455-0217. [email protected]. Information on purchasing reprints may be separate strains of mice: CD-1 Institute of Cancer Re- found at www.anesthesiology.org or on the masthead page at the beginning of ␣ search (ICR) outbred mice, mice deficient in the 2AAR this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for ␣ personal use only, 6 months from the cover date of the issue. or the 2CAR subtype, and their wild-type (WT) controls. Anesthesiology, V 110, No 3, Mar 2009 638 CLONIDINE–DEXMEDETOMIDINE SYNERGY IN MICE 639 Further, the potential for cross-tolerance between the ago- Nociceptive Assay nists was assessed after chronic intrathecal delivery of ei- Nociceptive responsiveness was tested in the SP noci- ther agonist. Finally, the interaction between clonidine and ceptive test. The SP assay is a sensitive indicator of dexmedetomidine on a measure of sedation and motor milder analgesics.12 SP (10–20 ng) was injected intra- coordination (accelerating rotarod) was also evaluated. thecally to produce approximately 40–60 behaviors (scratches and bites directed to the hindquarters) in the first minute after injection. The dose of SP required to Methods and Materials produce this number of behaviors was confirmed with Animals each new experiment. Coadministration of opioid or Experimental subjects were 20- to 25-g male ICR mice adrenergic analgesics dose-dependently inhibits those 13 (Harlan, Madison, WI) or 15- to 20-g male and female mice behaviors. To test the ability of dexmedetomidine and Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/110/3/638/368471/0000542-200903000-00032.pdf by guest on 26 September 2021 (sex matched) with either a mixed C57BL/6-129/Sv genetic clonidine to inhibit SP-induced behavior, the drugs were ␣ ␣ background ( 2AAR-WT or 2AAR-D79N) or a pure coadministered with SP and inhibition was expressed as ␣ ␣ C57BL/6 background ( 2CAR-WT or 2CAR-knockout a percent of the mean response of the control group [KO]). Animals were maintained on a 12-h light/dark cycle (determined with each new experiment) according to ␣ and had unlimited access to food and water. The 2AAR- the following equation: D79N mutant mice had been generated by hit-and-run gene % Inhibition targeting as previously described8 on a hybrid C57BL/6- 129/Sv background. WT animals of the same mixed back- ϭ ͓͑Control Ϫ Experimental͒ ⁄ Control͔ ϫ 100. ␣ ␣ ground were used as controls ( 2AAR-WT). The 2CAR-KO mice were developed at Stanford University, Palo Alto, Sedation/Motor Impairment Assay California,9 and were purchased from Jackson Labs, Bar In the same mice that received SP stimulation, doses of Harbor, Maine, after 17 generations of backcrossing to clonidine, dexmedetomidine, and their combination C57BL/6 background. C57BL/6 mice pair-bred within our were tested for impairment of rotarod performance. In ␣ facility were used as WT controls ( 2CAR-WT). Breeding such experiments, the animals were trained the day pairs were established, and pups were weaned between 2 before experimentation to walk 300 s on the accelerat- and 3 weeks of age. Within each experiment, animals were ing rotarod, typically requiring three trials to learn the age- and sex-matched across groups. Animals were used no behavior. The following
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