Neuronal H4 histamine receptors: role in nociceptive pathways and pain states

Abstract

The Histamine H4 receptor (H4R) is a classic G-protein coupled receptor (GPCR) and is expressed on a range of cell types in the body. To determine the roles of the H4R in the peripheral and central nervous system, four hypotheses have been addressed. (1) The H4R are expressed on sensory neurons in the peripheral and central nervous system; (2) The H4R is differentially expressed during acute inflammatory and neuropathic pain states; (3) Antagonism of the H4R with the antagonist JNJ 7777120 ameliorates central inflammation observed during experimental autoimmune encephalomyelitis (EAE); (4) Antagonism of the central H4R with JNJ 777120 has anxiolytic effects and improves memory performance in mice.
Based on immunofluorescence approaches we have demonstrated for the first time the presence of the H4R on both putative A-delta (Aδ) and C-fibre sensory neurons in the skin and dorsal root ganglia. Using the novel agonist selective H4R agonist, VUF 8430 revealed functional expression of H4R on primary rodent dorsal root ganglia neurons. Using quantitative immunoblotting, we provide preliminary evidence for the rodent H4 receptor bilateral and unilateral upregulation in the skin, but not the spinal cord in the acute phase of Complete Freund’s adjuvant induced inflammatory pain and nerve constriction acute neuropathic pain, respectively.
The H4R is an attractive target for the treatment of many inflammatory disorders. However, in contrast to the beneficial anti-inflammatory effects of H4R antagonism observed in literature, blockade of the receptor using JNJ 7777120 in acute EAE (autoimmune disease) appeared to exacerbate the pathology, and increased spinal cord inflammation, demyelination, microglia activation and functional deficits. Antagonism of the central H4R with JNJ 7777120 at 10 and 20 mg/kg (i.p.) appears to affect the behaviour of Balb/c mice but there is no indication of altering anxiety or non-spatial memory performance. However, the study did provide preliminary evidence for central behavioural effects with regard to time spent in the central part of the platform. Overall, this thesis provides new evidence for multiple roles of the H4R in the mammalian central and sensory neurons.