Histamine H₃ receptor blockade alleviates neuropathic pain through the regulation of glial cells activation

Neuropathic pain is a disorder affecting the somatosensory nervous system. However, this condition is also characterized by significant neuroinflammation, primarily involving CNS-resident non-neuronal cells. A promising target for developing new analgesics is histamine H₃ receptor (H₃R); thus, we aimed to determine the influence of a novel H₃R antagonist/inverse agonist, E-98 (1-(7-(4-chlorophenoxy)heptyl)-3-methylpiperidine), on pain symptoms and glia activation in model of neuropathic pain in male mice (chronic constriction injury to the sciatic nerve). We investigated the effects of single intraperitoneal (i.p.) (1, 5, 10, 20 mg/kg) and intrathecal (i.th.) (10, 30, 60 µg/5 µL) E-98-injections on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli. The effect of chronic E-98 (10 mg/kg, i.p.) treatment and its influence on glia activation within the lumbar spinal cord was investigated. The anti-inflammatory properties of E-98 (10 µM) were screened in primary microglial and astroglial cell cultures. We assessed the presence of H₃R within the spinal cord of control and neuropathic animals and in cell cultures. E-98 attenuated nociceptive responses in a dose- and time-dependent manner, and this effect is correlated with reduced microglia and increased astroglia activation. In vitro studies showed a decreased pro-inflammatory IL-6 level in both cell cultures. We observed co-localization of H₃R with spinal neurons, microglia, and astrocytes and in primary glial cell cultures. We suggest that an analgesic effect of E-98 is partially due to the modulation of glial activation. We explore a new mechanism of H₃R antagonists/inverse agonists analgesic action, bringing the potential benefits in pain management strategies.