Antipruritic Effects of Kappa Opioid Receptor Agonists: Evidence from Rodents to Humans
Centrally administered bombesin induces scratching and grooming in rats. These behaviors were blocked by early benzomorphan kappa opioid receptor (KOR) agonists as reported by Gmerek and Cowan in 1984. This was the first evidence that KORs may be involved
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Contents 1 Introduction 2 A Brief Introduction to the Field of Itch 2.1 Terminology and Classification of Itch 2.2 Animal Models of Itch 3 KORs Are Involved in the Sensation of Itch 3.1 Kappa Opioid Receptor Antagonists Evoke Scratching in Mice 3.2 Antipruritic Effects of Kappa Opioid Receptor Agonists Against Different Pruritogens 4 Conclusions References
Abstract
Centrally administered bombesin induces scratching and grooming in rats. These behaviors were blocked by early benzomorphan kappa opioid receptor (KOR) agonists as reported by Gmerek and Cowan in 1984. This was the first evidence that KORs may be involved in the sensation of itch-like behaviors. Subsequent development of additional animal models for acute and chronic itch has led to important discoveries since then. For example, it was found that (a) gastrinreleasing peptide (GRP), natriuretic polypeptide b and their cognate receptors are keys for the transmission of itch sensation at the spinal cord level, (b) dynorphins (Dyns), the endogenous KOR agonists, work as inhibitory neuromodulators of itch at the spinal cord level, (c) in a mouse model for acute itch, certain KOR antagonists elicit scratching, (d) in mouse models of acute or
S. Inan (*) · A. Cowan Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_420
S. Inan and A. Cowan
chronic itch, KOR agonists (e.g., U50,488, nalfurafine, CR 845, nalbuphine) suppress scratching induced by different pruritogens, and (e) nalfurafine, CR 845, and nalbuphine are in the clinic or in clinical trials for pruritus associated with chronic kidney disease and chronic liver disease, as well as pruritus in chronic skin diseases. Keywords
50 -GNTI · Animal models of itch · Difelikefalin · Itch · Kappa opioid receptor agonist · Kappa opioid receptor antagonist · Nalbuphine · Nalfurafine · norBNI
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Introduction
There have been great advances in the field of itch research since its first-time description by the German physician, Samuel Hafenreffer (1587–1660), in a 1660 dermatology textbook as “an unpleasant sensation that provokes the desire to scratch.” Historically, written medical mention of itch was first recorded in an Egyptian papyrus (Mueller et al. 2020). When the word “itch” was searched in PubMed, 26,136 studies were listed (until June 2020). Figure 1 summarizes the number of publications, both clinical and preclinical, reported in 10-year periods, beginning from 1940. The figure clearly shows that by the beginning of the1990s interest in itch research intensified. This might have been due to (a) a mouse model for itch developed by Kuraishi et al. (1995), (b) the founding of the International Forum for the Study of Itch (IFSI) in 2005, a scientific organization that brings together clinical and preclinical researchers studying itch, (c) advances in genetic 11000 Number of publica
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