Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice

Abstract

Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scratching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior.

Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non‐histaminergic pruritus

“…Further, the effectiveness of ultraviolet radiation in reducing pruritus in atopic dermatitis and uremic pruritus may relate to the suppression of TNF‐ α ‐iNOS linkage leading to reduced NO . These results establish the common role of NO both in CQ itching as well as in other forms of chronic itch.…”

“…In further experiments, the antagonism of N ‐methyl‐ d ‐aspartate (NMDA) receptors (which release NO) reduced intradermal CQ‐induced scratching frequency and intensity in mice, whilst the NMDA agonist potentiated CQ scratching and neuronal action potentials . There was a synergistic inhibitory effect, both of NMDA receptor antagonist and nitric oxide synthase inhibitor ( l ‐NAME) to reduce the frequency of CQ pruritus with reduction in CQ‐induced rise in cerebral nitrite levels in mice .…”

“…Nitric oxide (NO) and the cyclic guanosine monophosphate (GMP) pathway have recently been implicated in CQ itching in mice . Scratching following CQ in mice was shown to be attenuated by nitric oxide synthase inhibitor l ‐NAME, and by neuronal nitric oxide synthase inhibitor 7‐nitro‐indazole, but accentuated by l ‐arginine and by sildenafil, the Phospho‐diesterase 5 (PDE‐5) inhibitor, both of which raise c‐GMP levels …”

Characterization of the chloroquine‐induced mouse model of pruritus using an automated behavioural system

“…A reduced effect of the H1 receptor antagonist desloratadine administered i.p. has also been reported in the model . However, only their effect on scratching and not their effect on locomotion was assessed.…”

Development of resistance to serotonin‐induced itch in bile duct ligated mice

“…After open field tests, the assessments of scratching behaviour were done as described in previous studies. [48][49][50][51][52] Mice were held in private small Plexiglas chambers (10 cm×10 cm×13 cm) 60 minutes before experiments to adapt to the chamber. Animals could not see each other during the experiments.…”