Journal of Pharmacological Sciences 132 (2016) 113e114

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Journal of Pharmacological Sciences

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Letter Nalfurafine hydrochloride, a selective k opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys

that there are species differences in functional selectivity of Keywords: Nalfurafine several full agonists, which raises the possibility that results ob- k opioid receptor tained from one species with k opioid receptor agonists may not Rhesus monkeys be applicable to the other (4). Pruritus The behavioral actions of m and k agonists are not simply different, but in most aspects quite opposite (5). m Agonists such as morphine induce locomotor hyperactivity in most laboratory species, while k agonists cause overall locomotor depression in We read with interest and comment on mechanism of effect mice, rats, and monkeys (5). Contrary to the euphoriant action of from the paper by Nakao and colleagues (1), entitled “Nalfurafine m opioids, k-agonists are aversive and dysphoric (5). hydrochloride, a selective k opioid receptor agonist, has no rein- A recent review paper by Shigeki Inui (6) concludes that nalfur- forcing effect on intravenous self-administration in rhesus mon- afine is safe and effective for the treatment of hemodialysis pa- keys”, published in the Journal of Pharmacological Sciences.The tients with uremic pruritus resistant to antihistamines. authors suggest that while nalfurafine is a potent and selective Interestingly, of all the adverse effects reported during a 52- agonist at the k opioid receptor, it also possesses weak and partial week long-term trial by patients, which included insomnia agonist activity at m opioid receptors. Given that opioids, especially (15.2%), constipation (3.3%), somnolence (1.9%), dizziness (0.9%), those acting at m receptors, carry a potential risk of abuse, Nakao pruritus (0.9%), diarrhea (0.9%), malaise (0.9%), mood alteration et al. evaluated the reinforcing effects of nalfurafine by intrave- (0.9%), etc., there was no reported incidence of psychotomimetic nous self-administration of nalfurafine in rhesus monkeys. The or dysphoric effects (6). investigation has demonstrated that nalfurafine has no reinforcing In reviewing this paper and the literature, it appears likely that effect in rhesus monkeys in an intravenous self-administration the results of the present investigation represent biased agonism, paradigm. Nakao et al. conclude that nalfurafine can be used for referring specifically to the ability of a ligand to activate a subset the treatment of intractable pruritus in hemodialysis or chronic of a receptor's signaling cascade (7). This concept has recently liver disease patients with minimal concern regarding the risk of been reviewed at the kappa opioid receptor by Dogra and Yadav drug abuse (1). (8) and may help to better explain the unexpected result that However, a few decades ago, the agonism of the k opioid recep- none of the 211 patients reported any psychotomimetic and tor was shown to elicit dysphoric and psychotomimetic effects in dysphoric effects, realizing that k agonism in humans is known to humans (2,3). In a paper by Pfeiffer et al., the psychotomimetic ef- elicit these types of adverse effects. fects which subjects reported included racing thoughts, feelings of body distortion, disturbances in the perception of space and time, abnormal visual experiences, including moving lines or walls or co- External funding lor phenomena, and uncontrolled laughter. We question how, and if, such psychotomimetic experience would be manifested in rhesus None. monkeys. Further, Nakao et al. reason that animal studies of abuse liabil- Conflict of interest ity have the advantages of utilizing a wider range of doses and fi including a positive control drug. Nalfura ne does not induce The authors indicated no potential conflicts of interest. conditioned place preference in mice or rats, indicating that the drug does not produce a rewarding effect (1). However, DiMattio and colleagues (4) have recently demonstrated k opioid receptor k agonists display functional selectivity at both human opioid re- References ceptor and mouse k opioid receptor in neuro-2a mouse neuroblas- toma cells. They conclude that the novel finding in their study is (1) Nakao K, Hirakata M, Miyamoto Y, Kainoh M, Wakasa Y, Yanagita T. Nalfurafine hydrochloride, a selective k opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys. J Pharmacol Sci. 2016 Jan;130(1):8e14. (2) Pfeiffer A, Brantl V, Herz A, Emrich HM. Psychotomimesis mediated by kappa Peer review under responsibility of Japanese Pharmacological Society. opiate receptors. Science. 1986;233(4765):774e776. http://dx.doi.org/10.1016/j.jphs.2016.05.007 1347-8613/© 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 114 Letter / Journal of Pharmacological Sciences 132 (2016) 113e114

(3) Walsh SL, Strain EC, Abreu ME, Bigelow GE. Enadoline, a selective kappa opioid Stanley Martin Hall agonist: comparison with butorphanol and hydromorphone in humans. Psy- Department of Anesthesiology, Children's Hospital, 200 Henry Clay chopharmacology (Berlin). 2001;157(2):151e162. (4) DiMattio KM, Ehlert FJ, Liu-Chen L-Y. Intrinsic relative activities of k opioid ag- Avenue, New Orleans, LA 70118, USA onists in activating Ga proteins and internalizing receptor: differences between E-mail address: [email protected]. human and mouse receptors. Eur J Pharmacol. 2015;761:235e244. (5) Szekely JI. Opioid peptides in substance abuse, vol. 8. CRC Press; 1993. p. 1e7. Alan David Kaye Chapter 1. Department of Anesthesiology, Louisiana State University Health (6) Inui S. Nalfurafine hydrochloride to treat pruritus: a review. Clin Cosmet Inves- tig Dermatol. 2015;8:249e255. Science Center, 1542 Tulane Ave, New Orleans, LA 70112, USA (7) Andresen BT. A pharmacological primer of biased agonism. Endocr Metab Im- E-mail address: [email protected]. mune Disord Drug Targets. 2011 Jun;11(2):92e98. (8) Dogra S, Yadav PN. Biased agonism at kappa opioid receptors: implication in * pain and mood disorders. Eur J Pharmacol. 2015;763:184e190. Corresponding author. E-mail address: [email protected] (X. Ruan). * Xiulu Ruan 2 February 2016 Department of Anesthesiology, Louisiana State University Health Available online 30 May 2016 Science Center, 1542 Tulane Ave, New Orleans, LA 70112, USA