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