The emerging therapeutic roles of κ-opioid agonists

Authors

  • Mark R. Jones, MD
  • Alan David Kaye, MD, PhD
  • Aaron J. Kaye, BA
  • Richard D. Urman, MD, MBA

DOI:

https://doi.org/10.5055/jom.2016.0321

Keywords:

κ-opioid, pain, opioid, analgesia, compound 9, CR845, PR-38

Abstract

The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the κ-opioid (KOP) receptor, have long been known to play a role in pain relief.

Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established κ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.

Author Biographies

Mark R. Jones, MD

Medical Student, Tulane University School of Medicine, New Orleans, Louisiana

Alan David Kaye, MD, PhD

Professor and Chairman, Department of Anesthesiology, LSU School of Medicine, New Orleans, Louisiana.

Aaron J. Kaye, BA

Medical Student, Medical University of South Carolina, Charleston, South Carolina

Richard D. Urman, MD, MBA

Associate Professor, Harvard Medical School, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

References

Deyo RA, et al.: Report of the National Institutes of Health task force on research standards for chronic low back pain. J Manipulative Physiol Ther. 2014; 37(7): 449-467.

Global Burden of Disease Study 2013 Collaborators: Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 386(9995): 743-800.

Hughes FM Jr, Shaner BE, Brower JO, et al.: Development of a peptide-derived orally-active kappa-opioid receptor agonist targeting peripheral pain. Open Med Chem J. 2013; 7: 16-22.

Stein C, Clark JD, Oh U, et al.: Peripheral mechanisms of pain and analgesia. Brain Res Rev. 2009; 60(1): 90-113.

Stein C, Machelska H: Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev. 2011; 63(4): 860-881.

Busch-Dienstfertig M, Stein C: Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain—basic and therapeutic aspects. Brain Behav Immun. 2010; 24: 683-694.

Riviere PJ: Peripheral kappa-opioid agonists for visceral pain. Br J Pharmacol. 2004; 141: 1331-1334.

Kivell B, Prisinzano TE: Kappa opioids and the modulation of pain. Psychopharmacology (Berl). 2010; 210(2): 109-119.

Peckys D, Landwehrmeyer GB: Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study. Neuroscience. 1999; 88: 1093-1135.

Rau KK, Caudle RM, Cooper BY, et al.: Diverse immunocyto-chemical expression of opioid receptors in electro- physiologically defined cells of rat dorsal root ganglia. J Chem Neuroanat. 2005; 29: 255-264.

Janson W, Stein C: Peripheral opioid analgesia. Curr Pharm Biotechnol. 2003; 4: 270-274.

Stein C, Hassan AH, Przewlocki R, et al.: Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci USA. 1990; 87: 5935-5939.

Burton MB, Gebhart GF: Effects of intracolonic acetic acid on responses to colorectal distension in the rat. Brain Res. 1995; 672: 77-82.

Burton MB, Gebhart GF: Effects of kappa-opioid receptor agonists on responses to colorectal distension in rats with and without acute colonic inflammation. J Pharmacol Exp Ther. 1998; 285: 707-715.

Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980; 69: 503-512.

Obara I, Parkitna JR, Korostynski M, et al.: Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain. Pain. 2009; 141: 283-291.

Xu M, Petraschka M, McLaughlin JP, et al.: Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci. 2004; 24: 4576-4584.

Feng Y, He X, Yang Y, et al.: Current research on opioid receptor function. Curr Drug Targets. 2012; 13(2): 230-246.

Martin WR, Eades CG, Thompson JA, et al.: The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976; 197: 517-532.

Rothman RB, Bykov V, Decosta BR, et al.: Interaction of endogenous opioid peptides and other drugs with four kappa opioid binding sites in guinea pig brain. Peptides. 1990; 11: 311-331.

Filizola M, Devi LA: Grand opening of structure-guided design for novel opioids. Trends Pharmacol Sci. 2013; 34(1): 6-12.

Vanderah TW, Largent-Milnes T, Lai J, et al.: Novel d-amino acid tetrapeptides produce potent antinociception by selectively acting at peripheral kappa-opioid receptors. Eur J Pharmacol. 2008; 583(1): 62-72.

Chalmers DT, Jones JB, Spencer RH: Peripheral kappa receptor agonists for reducing pain and inflammation. WO2013184794 A2. June 5, 2013.

Arendt-Nielsen L, Olesen AE, Staahl C, et al.: Analgesic efficacy of peripheral kappa-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain. Anesthesiology. 2009; 111(3): 616-624.

Cara Therapeutics: Available at http://www.caratherapeutics.com/. Accessed October 13, 2015.

Sałaga M, Polepally PR, Sobczak M, et al.: Novel orally available salvinorin A analog PR-38 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome. J Pharmacol Exp Ther. 2014; 350(1): 69-78.

Sałaga M, Polepally PR, Zakrzewski PK, et al.: Novel orally available salvinorin A analog PR-38 protects against experimental colitis and reduces abdominal pain in mice by interaction with opioid and cannabinoid receptors. Biochem Pharmacol. 2014; 92(4): 618-626.

Inan S, Cowan A: Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats. Pharmacol Biochem Behav. 2006; 85: 39-43.

Taneda K, Tominaga M, Negi O, et al.: Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch. Br J Dermatol. 2011; 165: 277-284.

Tominaga M, Ogawa H, Takamori K: Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. J Invest Dermatol. 2007; 127: 2228-2235.

Attali B, Saya D, Vogel Z: Kappa-opiate agonists inhibit adenylate cyclase and produce heterologous desensitization in rat spinal cord. J Neurochem. 1989; 52: 360-369.

Prather PL, McGinn TM, Claude PA, et al.: Properties of a kappa-opioid receptor expressed in CHO cells: interaction with multiple G-proteins is not specific for any individual G alpha subunit and is similar to that of other opioid receptors. Brain Res Mol Brain Res. 1995; 29: 336-346.

Wang GY, Wu S, Pei JM, et al.: Kappa- but not delta-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol. 2001; 280: H384-H391.

Liu JC, Yin W, Yin Z, et al.: Anti-arrhythmic effects of -opioid receptor and its changes in ischemia and reperfusion. Arch Med Res. 2008; 39: 483-488.

Tong G, Sun ZC, Wei XF, et al.: U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion. Life Sci. 2011; 88: 31-38.

Webster LR, Menzaghi F, Spencer RH: CR845, a novel peripherally acting kappa opioid receptor agonist, has low abuse potential compared with pentazocine. Presented at APS Annual Meeting 2015, PRA Health Sciences, Salt Lake City, UT.

Stauffer JW, Spencer RH, Menzaghi F: CR845, a peripheral kappa opioid, provides better pain relief with less nausea and vomiting than placebo in patients after bunionectomy. Presented at APS Annual Meeting 2015, Cara Therapeutics, Inc., Shelton, CT, USA.

Stauffer JW, Spencer RH, Menzaghi F: Efficacy of the peripheral kappa opioid agonist CR845 in laparascopic hysterectomy. Presented at AAPM Annual Meeting 2015. Cara Therapeutics, Inc., Shelton, CT, USA.

John TF, French LG, Erlichman JS: The antinociceptive effect of Salvinorin A in mice. Eur J Pharmacol. 2006; 545: 129-133.

Ansonoff MA, Zhang J, Czyzyk T, et al.: Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice. J Pharmacol Exp Ther. 2006; 318: 641-648.

Phan NQ, Lotts T, Antal A, et al.: Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol. 2012; 92(5): 555-560.

Zhang QY, Wang W, Shi QX, et al.: Antiarrhythmic effect mediated by -opioid receptor is associated with Cx43 stabilization. Crit Care Med. 2010; 38: 2365-2376.

Yu XC, Li HY, Wang HX, et al.: U50488H inhibits effects of norepinephrine in rat cardiomyocytes-cross-talk between opioid and -adrenergic receptors. J Mol Cell Cardiol. 1998; 30: 405-413.

Published

03/01/2016

How to Cite

Jones, MD, M. R., A. D. Kaye, MD, PhD, A. J. Kaye, BA, and R. D. Urman, MD, MBA. “The Emerging Therapeutic Roles of κ-Opioid Agonists”. Journal of Opioid Management, vol. 12, no. 2, Mar. 2016, pp. 101-7, doi:10.5055/jom.2016.0321.