title: Antinociceptive effect of co-administered NMDA and histamine H4 receptor antagonists in a rat model of acute pain.
abstract: BACKGROUND
  The histamine H4 receptor (H4R) has attracted a lot of attention in terms of its role in antinociception. The N-Methyl-d-aspartic acid (NMDA) receptor is a well-characterized participant in pain pathways. However, it's influence on H4R signaling is poorly understood. Thus, in the present study we investigated the effect of a selective H4R antagonist JNJ7777120 (25mg/kg) and a NMDA receptor antagonist MK-801 (0.1-10μg) on nociceptive thresholds in a rat acute pain model.
  
  
  METHODS
  The influence of intrathecally (it), intracerebroventricularly (icv) and intraplantarly (ipl) administered MK-801 co-injected with JNJ7777120 administered intraperitoneally (ip) was determined in the modified Randall-Selitto paw pressure, the tail flick and plantar tests.
  
  
  RESULTS
  Both ip JNJ7777120 as well as MK-801 delivered it and ipl increased nociceptive pain thresholds. It and ipl pretreatment with MK-801 additively augmented JNJ7777120 mechanical antinociception. A weaker effect was also observed after it co-administration with MK-801 and JNJ7777120 in the tail flick test. Intracerebroventricular MK-801 failed to produce any effect nor did ipl MK-801 in the plantar test.
  
  
  CONCLUSIONS
  The results show for the first time that the H4R and NMDA receptors play a significant role in antinociception in an acute non-inflammatory pain. Furthermore, the blockage of NMDA receptors at the peripheral and spinal, but not supraspinal sites produces a profound antinociceptive response upon simultaneous H4R antagonism. Thus, this study clearly demonstrates the relevance of NMDA and H4R receptors in the modulation of pain signals and that their role is not exclusively limited to their modulatory activity in inflammatory pain states.
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland. Electronic address: renata_wolinska@op.pl.
authors.forename: Renata
authors.initials: R
authors.lastname: Wolińska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland. Electronic address: anna.lesniak@wum.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Leśniak
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland. Electronic address: mzochowska3@wp.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Żochowska
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland; Department of Genomics, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Magdalenka, Poland; Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warszawa, Poland. Electronic address: m.sacharczuk@ighz.pl.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Sacharczuk
authors.affiliation: Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian UniversityMedical College, Kraków, Poland. Electronic address: mfkonono@cyf-kr.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
authors.affiliation: Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland. Electronic address: mbujalska@gmail.com.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bujalska-Zadrożny
mesh_terms: D059787:Acute Pain / Q000188:drug therapy*; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D006633:Histamine Antagonists / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D010879:Piperazines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
chemical_list: D000700:Analgesics; D006633:Histamine Antagonists; C498828:Hrh4 protein, rat; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate
keywords: Analgesia; H4R histamine receptor antagonist; NMDA receptor antagonist; Pain