Abstract
Pruritus (itch) is a severe side effect associated with the use of drugs as well as hepatic and hematological disorders. Previous studies in rodents suggest that bombesin receptor subtypes i.e. receptors for gastrin-releasing peptide (GRPr) and neuromedin B (NMBr) differentially regulate itch scratching. However, to what degree spinal GRPr and NMBr regulate scratching evoked by intrathecally administered bombesin-related peptides is not known. The first aim of this study was to pharmacologically compare the dose-response curves for scratching induced by intrathecally administered bombesin-related peptides versus morphine, which is known to elicit itch in humans. The second aim was to determine if spinal GRPr and NMBr selectively or generally mediate scratching behavior. Mice received intrathecal injection of bombesin (0.01–0.3 nmol), GRP (0.01–0.3nmol), NMB (0.1–1nmol) or morphine (0.3–3 nmol) and were observed for one hour for scratching activity. Bombesin elicited most profound scratching over one hour followed by GRP and NMB, whereas morphine failed to evoke scratching response indicating the insensitivity of mouse models to intrathecal opioid-induced itch. Intrathecal pretreatment with GRPr antagonist RC-3095 (0.03–0.1 nmol) produced a parallel rightward shift in the dose response curve of GRP-induced scratching but not NMB-induced scratching. Similarly, PD168368 (1–3 nmol) only attenuated NMB but not GRP-induced scratching. Individual or co-administration of RC-3095 and PD168368 failed to alter bombesin-evoked scratching. A higher dose of RC-3095 (0.3 nmol) generally suppressed scratching induced by all three peptides but also compromised motor function in the rotarod test. Together, these data indicate that spinal GRPr and NMBr independently drive itch neurotransmission in mice and may not mediate bombesin-induced scratching. GRPr antagonists at functionally receptor-selective doses only block spinal GRP-elicited scratching but the suppression of scratching at higher doses is confounded by motor impairment.
Highlights
Itch is an unpleasant sensation, which provokes the desire to scratch
We demonstrated that at the supraspinal level, gastrin-releasing peptide receptor (GRPr) and neuromedin-B receptor (NMBr) independently mediate scratching
The main goals of this study were (a) to pharmacologically characterize the dose-response curves and duration of scratching induced by intrathecally administered bombesin-related peptides such as bombesin, gastrin-releasing peptide (GRP) and neuromedin B (NMB) as well as morphine in mice and, (b) to determine whether GRPr and NMBr in the spinal cord independently or mutually regulate scratching evoked by bombesin-related peptides using the selective GRPr and NMBr antagonists
Summary
Itch (pruritus) is an unpleasant sensation, which provokes the desire to scratch. Despite being a significant medical burden, the effective management of pruritus poses a major challenge due to the lack of broad-spectrum antipruritic drugs. Commonly prescribed antipruritic drugs such as topical emollients and antihistamines fail to relieve chronic itch [2,6]. Such hurdles are largely due to the poor understanding of the biological mechanisms that drive the sensation of itch. More preclinical research is warranted in order to identify the receptors that mediate itch and to characterize potential antipruritic drugs
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