INVESTIGATIVE REPORT
571 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Peripheral NMDA Receptor / NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice
Nazgol-Sadat HADDADI 1 , 2 , 4 , Arash FOROUTAN 1 , 3 , Sattar OSTADHADI 1 , 2 , 5 , Ehsan AZIMI 6 , Nastaran RAHIMI 1 , 2 , Mehdi NATEGHPOUR 4 , Ethan A . LERNER 6 and Ahmad Reza DEHPOUR 1 – 3
1
Experimental Medicine Research Center , 2 Department of Pharmacology , School of Medicine , 3 Faculty of Pharmacy , 4 Department of Medical Parasitology and Mycology , School of Public Health , 5 Brain and Spinal Cord Injury Research Center , Neuroscience Institute , Tehran University of Medical Sciences , Tehran , Iran and 6 Department of Dermatology , Cutaneous Biology Research Center , Massachusetts General Hospital , Boston , USA
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 scrat ching behavior . While intradermal administration of CQ significantly increases the concentration of intra dermal 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 CQinduced scratching behavior .
Key words : itch ; chloroquine ; N-methyl-D-aspartate receptor ( NMDA ) antagonists ; nitric oxide ; mice .
Accepted Jan 24 , 2017 ; Epub ahead of print Jan 25 , 2017 Acta Dem Venereol 2017 ; 97 : 571 – 577 .
Corr : Ahmad Reza Dehpour , Department of Pharmacology , School of Medicine , Tehran University of Medical Sciences , Poorsina St ., Enghelab Ave ., PO Box : 13145-784 , Tehran , Iran . E-mail : dehpour @ yahoo . com
Chloroquine ( CQ ) has been used to treat malaria , certain viral infections ( 1 ) and a number of autoimmune diseases including rheumatoid arthritis ( 2 ) and systemic lupus erythematosus ( 3 ). Chloroquine also induces itch in humans and scratching in mice ( 4 , 5 ) via a histamine-independent pathway linked to activation of Mrgprs ( 6 ). Chloroquine activates human MRGPRX1 and the homologous mouse receptor , MrgprA3 ( 6 ). As expected , CQ-induced scratching behavior is diminished in Mrgpr cluster knockout mice , which lack MrgprA3 ( 7 ). In addition , the kappa-opioid agonist , nalfurafine , has been shown to decrease CQ-induced scratching behavior in mice ( 8 ). MrgprA3 coupling to G βγ modulates
TRPA1 to result in itch ( 6 , 9 ). G βγ modulates several ion channels via direct binding ( 10 ). The N-methyl-daspartate receptor ( NMDAR ) is a non-selective cation ion channel ( 11 ). NMDAR is implicated in synaptic plasticity , memory ( 11 , 12 ) and pain ( 13 , 14 ). The administration of NMDA or glutamate to the rat hind paw evokes nociceptive behaviors that are decreased by the injection of NMDAR antagonists in the periphery ( 14 , 15 ). Peripherally-acting NMDAR antagonists have been used for inflammatory and visceral pain and seem to be devoid of CNS side effects ( 16 ) while oral administration of gabapentin and pregabalin act centrally and are used to treat the neuropathic itch associated with brachioradial and post-herpetic pruritus ( 17 – 21 ).
Intrathecal injection of NMDA induces scratching behavior in mice ( 22 ) while NMDAR antagonists suppress such behavior ( 17 , 23 ). The physiology is analogous in rats , where intrathecal administration of the NMDAR antagonists ketamine and kynurenic acid decrease scratching behavior induced by intradermal injection of the serotonin derivative 5-methoxytryptamine ( 23 ). Intrathecal application of the NMDAR antagonists dizocilpine ( MK-801 ) or D ( - ) -2-amino- 5-phosphonovalerate ( APV ) prevented intracutaneous histamineinduced expansion of mechanical receptive fields in rats ( 24 ). Separately , it has been shown that administration of a nitric oxide ( NO ) donor to skin enhances substance P-induced itch in mice ( 25 ), while serotonin-induced itch was inhibited by systemic nitric oxide synthase ( NOS ) inhibitors ( 26 ).
Taken together , previous reports have revealed that activation of the NMDA / NO pathway is associated with pain ( 27 ) while inhibition of this pathway decreases pain and itch ( 23 , 25 , 27 ). Activation of this pathway is also associated with increased NO production ( 28 ), which itself is linked to cGMP ( 29 ). NO production is associated with itch while inhibition of NOS suppresses itch . We reported recently that the NO / cGMP pathway participates in CQ-induced itch ( 30 ). Here we extend these findings with the demonstration that the NMDA / NO pathway participates in CQ-induced scratching behavior .
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2017 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2617 Acta Derm Venereol 2017 ; 97 : 571 – 577