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Analgesic and Antiinflammatory Effects of Two Novel Κ-Opioid

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Analgesic and Antiinflammatory Effects of Two Novel Κ-Opioid Anesthesiology 2001; 94:1034–44 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Analgesic and Antiinflammatory Effects of Two Novel ␬-Opioid Peptides Waltraud Binder, Ph.D.,* Halina Machelska, Ph.D.,* Shaaban Mousa, Ph.D.,* Thomas Schmitt, M.D.,* Pierre J. M. Rivière, Ph.D.,† Jean-Louis Junien, Ph.D.,‡ Christoph Stein, M.D.,§ Michael Schäfer, M.D.ʈ Background: This study investigates two new ␬-agonist tet- mediates specific additional responses. For example, eu- rapeptides, FE 200665 and FE 200666, with high peripheral phoria, physical dependence, and respiratory depression selectivity as a result of poor central nervous system are mainly associated with ␮ and ␦ receptors.1 Spinal, penetration. ␮ Methods: Four days after administration of Freund adjuvant supraspinal, and peripheral -receptors also mediate opi- into the hind paw of male Wistar rats, antinociceptive effects of oid-induced gastrointestinal transit inhibition and consti- intraplantar and subcutaneous injection of FE 200665 and FE pation.3 In contrast, opioids acting at ␬-receptors pro- 200666 were measured by paw pressure algesiometry and com- duce dysphoric rather than euphoric effects, which ␬ ␬ pared with the -agonist U-69,593. Peripheral and -receptor limits their dependence liability and produces little or no selectivity was assessed by the antagonists naloxone methio- ␬ dide (NLXM) and nor-binaltorphimine, respectively. Antiin- respiratory depression. Furthermore, -agonists do not flammatory effects were evaluated by paw volume plethysmom- inhibit intestinal transit or induce constipation. Thus, etry and histologic score. ␬-opioids offer advantages in comparison to ␮-opioids Results: Similar to intraplantar U-69,593, intraplantar FE and are currently being pursued as analgesic agents. ␮ ␮ 200665 (3–100 g) and FE 200666 (1–30 g) resulted in signifi- However, centrally acting ␬-opioids can produce psy- cant and dose-related increases of paw pressure thresholds. 4 Higher doses of FE 200665 (0.2–20 mg) and FE 200666 (0.06– chotomimesis and may be aversive in humans. A poten- 6 mg) were required by subcutaneous route to produce similar tially successful strategy to eliminate the adverse side ef- antinociceptive responses, supporting a peripheral site of ac- fects of ␬-opioids is to restrict the access of these tion. nor-Binaltorphimine dose-dependently antagonized this compounds to the central nervous system, as opioid anal- ␬ effect, implying -opioid selectivity. Analgesic effects of subcu- gesia can also be brought about by the activation of opioid taneous FE 200665 and FE 200666 were abolished by intraplan- tar nor-binaltorphimine, and both subcutaneous and intraplan- receptors on peripheral nerve endings, particularly during 5–7 tar effects were dose-dependently antagonized by subcutaneous inflammatory conditions. Clinical studies have shown NLXM, further demonstrating a peripheral site of action. One to that intraarticular morphine relieves acute postoperative as 6 days after Freund adjuvant inoculation, single and repeated well as chronic arthritic pain.8 The analgesic effect is long- intraplantar injections of FE 200665, FE 200666, and U-69,593 lasting, e.g., up to 2 and 7 days, respectively. This is not significantly reduced paw volume and histologic scores. Both changes were reversed by intraplantar nor-binaltorphimine only explained by an inhibition in pain transmission but 8 and subcutaneous NLXM. also by a local antiinflammatory effect. Conclusion: FE 200665 is a peripherally selective ␬-agonist Previous attempts to design peripherally selective with potent analgesic and antiinflammatory properties that ␬-agonists have not been successful. These attempts may lead to improved analgesic–antiinflammatory therapy were based on small organic molecules. Recently, novel compared with centrally acting opioids or standard nonsteroi- ␬ dal antiinflammatory drugs. and peptidic -ligands were identified by positional scan- ning of a tetrapeptide combinatorial library screened in 9 OPIOID analgesics, despite their side effects, are unsur- opioid receptor radioligand binding assays. These new ␬ passed in the pharmacologic treatment of severe pain. -ligands have an all D-amino acids sequence and show ␬ They exert their diverse physiologic effects through high selectivity for the -receptor. Furthermore, this ␬ ␬ three distinct membrane-bound receptor subtypes—␮, new class of -ligands are potent -agonists in vitro, ␦, and ␬—in the central nervous system1 and in the potent antinociceptive agents in vivo, and peripherally 2 selective, as shown by the lack of sedative activity in the periphery. 10 In addition to analgesia, each opioid receptor subtype mouse rotarod after peripheral administration. How- ever, these series of new ␬-agonists are short-acting. Chemical optimization has led to the characterization of * Postdoctoral Fellow, § Professor and Chairman, ʈ Associate Professor, Depart- a second generation of tetrapeptide ␬-agonists with high ment of Anesthesiology and Critical Care Medicine, Klinikum Benjamin Franklin, peripheral selectivity and long duration of action.10 In Freie Universität Berlin. † Head of Biology, Ferring Research Institute Inc. ‡ Chief Scientific Officer, Ferring Pharmaceuticals. the current study we examined two of these novel com- Received from the Department of Anesthesiology and Critical Care Medicine, pounds, FE 200665 and FE 200666, which show high Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany; Ferring affinity subnanomolar and high selectivity for human Research Institute Inc., San Diego, California; and Ferring Pharmaceuticals, Paris, France. Submitted for publication July 31, 2000. Accepted for publication De- ␬-opioid receptor versus ␮-opiod receptor (up to 90,000- cember 1, 2000. Supported by Ferring Research Institute B.V., Hoofddorp, The fold) or ␦-opiod receptor (85,000-fold).10 The antinoci- Netherlands. Address reprint requests to Dr. Binder: Department of Anesthesiology and ceptive and antiinflammatory properties of these poten- Critical Care Medicine, Benjamin-Franklin University Hospital, Freie Universiät tially peripherally selective ␬-opioid peptides were Berlin, Hindenburgdamm 30, D 12200 Berlin, Germany. Address electronic mail ␬ to: [email protected]. Individual article reprints may be purchased assessed and compared with the standard -opioid through the Journal Web site, www.anesthesiology.org. U-69,593. Anesthesiology, V 94, No 6, Jun 2001 1034 Downloaded From: http://anesthesiology.pubs.asahq.org/pdfaccess.ashx?url=/data/Journals/JASA/931230/ on 07/08/2016 PERIPHERAL OPIOID ANALGESIA AND ANTIINFLAMMATION 1035 Materials and Methods (2) pannus formation (degree of intrusion of granulation tissue into the joint space); and (3) periosteal reaction Induction of Arthritis (extent of new bone formation). A rating scale from 0 to Experiments were conducted in male Wistar rats 8 was used for each variable (i.e., maximum obtainable weighing 250–300 g. Rats were housed individually and score ϭ 24). This procedure was based on the method- kept in a temperature-controlled room (22°C Ϯ 1) with ology originally described by Ackerman et al.11 a 12-h alternating light–dark cycle. To induce inflamma- tion, rats were sedated by brief halothane anesthesia and Drugs received an intraplantar injection of 150 ␮l Freund com- We used the ␬-opioid agonists U-69,593 (Sigma, De- plete adjuvant (FCA; Calbiochem, San Diego, CA) into isenhofen, Bavaria, Germany), FE 200665 and FE 200666 the right hind paw. Experiments and animal care were (Ferring Research, San Diego, CA), and the opioid antag- conducted in accordance with standard ethical guide- onists nor-binaltorphimine (nor-BNI) and naloxone me- lines (Tierschutz komission, Berlin, Germany). thiodide (NLXM; Sigma). All opioid drugs were dissolved in distilled water and administered intraplantarly Nociceptive Thresholds (100 ␮l), subcutaneously into a skin fold in the neck Between 4 and 6 days after induction of inflammation, (200 ␮l), or intrathecally (10 ␮l). Antagonists were given mechanical nociceptive thresholds were assessed using either concomitantly or 5 min before agonist administra- a paw pressure analgesymeter (Ugo Basile, Comerio, tion. Control animals received distilled water. Italy). The paw pressure threshold (PPT) required to elicit hind-paw withdrawal was determined by averaging Implantation of Intrathecal Catheters three consecutive trials separated by 10 s. The sequence Rats were handled and trained in the test situation for of left and right paws was alternated between animals to 3 days before intrathecal catherization. Anesthesia was avoid bias. The experimenter was blind to the conditions induced and maintained with 2% halothane via a loose- used. Data are represented as percent maximum possi- fitting plastic mask. The intrathecal catheters were pre- ble effect (MPE) with an arbitrary cutoff point of 250 g pared according to a method described previously.12 Ϫ and are calculated by the formula: (PPT treated PPT Briefly, a polyethylene tubing (PE-10; Portex, United Ϫ ϫ pretreated/250 PPT pretreated) 100. Kingdom) was cut in 200-mm lengths and inserted 15 mm in a cervical direction, through a previously made Evaluation of Inflammation incision at the L3–L4 level. The animals were allowed 4 Antiinflammatory effects were assessed by monitoring days to recover from anesthesia and surgery. During this paw volume with a plethysmometer (Ugo Basile) and by time, animals showing any sign of neurologic damage histologic examination.
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