jnj-10191584 and Disease-Models--Animal

The locus coeruleus (LC) adrenergic nuclei constitute a pain-control inhibitory system nucleus implicated in descending modulation of pain through the action on spinal α

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic Neurons; Animals; Benzimidazoles; Clonidine; Disease Models, Animal; Guanidines; Histamine; Humans; Injections, Spinal; Locus Coeruleus; Male; Mice; Mice, Knockout; Microinjections; Neuralgia; Norepinephrine; Pain Management; Receptors, Histamine H4; Thiourea

The effects of the highly selective histamine H4 receptor antagonists JNJ7777120 and VUF6002 were investigated on the carrageenan-induced inflammation and thermal hyperalgesia in rats. JNJ7777120 (10 and 30 mg/kg, s.c.) and VUF6002 (10 mg/kg, s.c.) significantly reduced paw edema and hyperalgesia provoked by subplantar injection of carrageenan; the effect was evident against the early (2 h) phase of inflammation. An inactive analog of VUF6002, VUF6007 (10 mg/kg, s.c.) slightly aggravated paw edema, while leaving unaltered carrageenan-induced nociception. These findings indicate that histamine H4 receptors participate in the early phase of acute inflammation induced by carrageenan in rats, influencing both edema and thermal hyperalgesia.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzimidazoles; Carrageenan; Disease Models, Animal; Edema; Histamine Antagonists; Hot Temperature; Hyperalgesia; Indoles; Inflammation; Male; Pain Measurement; Piperazines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Time Factors

Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.

Topics: Allergens; Animals; Benzimidazoles; CD4-Positive T-Lymphocytes; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Indoles; Inflammation; Lung; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Ovalbumin; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Respiratory Hypersensitivity