Pharmacological Analysis of GNTI-Induced Compulsive Scratching in Mice

Alan Cowan, Saadet Inan. Temple University School of Medicine, Philadelphia, PA 19140, United States.

Itch is a major symptom in several dermatological conditions as well as in cholestatic individuals and those undergoing haemodialysis. Management with antipruritic drugs is often so unsatisfactory that the unalleviated itch adversely affects the patients’ quality of life. Preclinical models of itch have relied on provoking vigorous hind leg scratching behaviour of mice in response to pruritic (as opposed to nociceptive) stimuli such as compound 48/80 and the attenuation of this reflex with the antihistamine, terfenadine, for example (Kuraishi et al., 1995; Sugimoto et al., 1998).

5′-Guanidinonaltrindole (GNTI, 0.03-1 mg/kg), the kappa opioid receptor antagonist, precipitates almost immediate stereotyped neck scratching after s.c. injection behind the neck of mice and this compulsive behaviour is attenuated when the animals are pretreated with nalfurafine (0.001-0.03 mg/kg, s.c.), the clinically tested antipruritic and kappa agonist (Inan et al., 2009).

What other pharmacological systems are involved in addition to this apparent kappa opioid link? We now report that histamine H-1 and H-4 antagonists, a gastrin releasing peptide receptor antagonist, and a muscarinic M-1 antagonist all had no marked blocking effects on the GNTI (0.30 mg/kg)-induced frenzied scratching. Thus, fexofenadine (20, 40 and 60 mg/kg, p.o. at -45 min), JNJ10191584 (10, 30 and 60 mg/kg, p.o. at -45 min), RC-3095 (10 mg/kg, i.p. at -15 min) and telenzepine (1, 3 and 10 mg/kg, s.c. at -30 min) did not decrease the mean number of scratching bouts (range = 355-492) displayed by the individually housed male, Swiss Webster mice (25-30 g; n = 5-8) in the 30 min after GNTI (0.30 mg/kg, s.c.). In contrast, McN-A-343, the muscarinic M-1 agonist (1.5, 5 and 15 μg/5 μl, i.t. at -10 min) caused dose-related and statistically significant antagonism of GNTI-induced excessive scratching (Table) without (per se) markedly affecting locomotor activity (Digiscan D Micro System, AccuScan).

Table Pretreating mice (n = 8) with McN-A-343 (1.5-15 μg, i.t. at -10 min) antagonizes compulsive scratching associated with GNTI (0.30 mg/kg, s.c.). *P<0.05; **P<0.01 vs. (saline + GNTI), ANOVA then Newman Keuls test.

Our results call attention to one of the most robust chemically induced behavioural syndromes in psychopharmacology and the initial experimental analysis of the underlying receptorology.

Inan, S. et al. (2009) Neuroscience, in press.
Kuraishi, Y. et al. (1995) Eur. J. Pharmacol. 275, 229-233.
Sugimoto, Y. et al. (1998) Eur. J. Pharmacol. 351, 1-5.

(Supported by NIDA #DA13429).