Figure 3.

Diagram illustrating histamine receptor signalling—G_i pathway. Histamine binds to the histamine receptors (presynaptic and postsynaptic H₃ or H₄ receptor subtypes) that are coupled with G_i‐type protein. The G_i α subunit inhibits AC with subsequent suppression of cAMP production and inhibition of PKA activity. Also, G_i β and γ subunits can inhibit Ca²⁺ influx through voltage‐gated N‐, P‐, and Q‐type Ca²⁺ channels and stimulate G protein‐coupled inwardly rectifying potassium (GIRK) channels, with resultant K⁺ efflux. Both effects on N‐type Ca²⁺ and GIRK channels result in the development of hyperpolarization, attenuation of neuronal excitability, and resultant pain relief. Besides G_i α subunit effects, H₃ receptor activation could produce analgesic effects through G_i β and γ subunits, which up‐regulate the PI3K pathway, with the subsequent production of phosphatidylinositol 2,4,5‐trisphosphate (PIP₃) from phosphatidylinositol 4,5‐bisphosphate (PIP₂). PIP₃ recruits PKB (Akt), which phosphorylates and inactivates glycogen synthase kinase 3β (GSK3β). In parallel, PKB (Akt)‐dependent phosphorylation additionally activates the MAPK/ERK cascade. The action on both GSK3β and MAPK/ERK decreases neuronal excitability, inhibits mechanisms of neuronal inflammation, and, therefore, produces pain relief