Antagonism of Supraspinal Histamine H₃ Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats

Abstract

There is growing evidence supporting a role for histamine H 3 receptors in the modulation of pathological pain. To further our understanding of this modulation, we examined the effects of a selective H 3 receptor antagonist, 6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide (GSK189254), on spinal neuronal activity in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of GSK189254 (0.03-1 mg/kg i.v.) dose-dependently decreased both evoked (10-g von Frey hair for 15 s) and spontaneous firing of wide dynamic range (WDR) neurons in neuropathic, but not sham-operated, animals. The effects on spontaneous firing suggest that H 3 receptors may have a role in central sensitization and/or modulating non-evoked pain. Transection of the spinal cord (T9-T10) completely eliminated the effects (both evoked and spontaneous) of systemic GSK189254 (1 mg/kg, i.v.) on WDR neuronal firing in neuropathic rats, indicating that the descending modulatory system has an important role in the H 3 -related dampening of spinal neuronal activity. Subsequently, lesions of the locus coeruleus, or direct GSK189254 (3 and 10 nmol/0.5 l) injections into this site, demonstrate that the locus coeruleus is a key component of the H 3 descending modulatory pathway. In summary, blockade of H 3 receptors reduces spontaneous firing as well as the responses of spinal nociceptive neurons to mechanical stimulation. This effect is in large part mediated via supraspinal sites, including the locus coeruleus, that send descending projections to modulate spinal neuronal activity.

A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain

“…WDR neurons spontaneously fired at a higher rate in neuropathic rats compared with the uninjured animals and is consistent with previous reports (Chu et al 2004;McGaraughty et al 2009McGaraughty et al , 2012Suzuki and Dickenson 2006). An increased level of spontaneous discharge in WDR neurons following tissue or nerve injury indicates spinal hyperexcitability and may also suggest that there is stimulus-independent ongoing pain in these animals (Chu et al 2004;Suzuki and Dickenson 2006).…”

“…The mean baseline spontaneous activity of WDR neurons in SNL rats was significantly higher (P Ͻ 0.01) than that in uninjured rats and is similar to levels reported previously (Chu et al 2004;McGaraughty et al 2012). C-fiber evoked responses were significantly elevated in SNL rats compared with the uninjured rats (P Ͻ 0.05); however, no other measure of evoked firing was different between the two groups.…”

Effects of microinjection of histamine into the anterior cingulate cortex on pain-related behaviors induced by formalin in rats

“…Moreover, Wei et al [5] reported that microinjection of A-960656, a histamine H 3 receptor antagonist, into the LC suppressed hypersensitivity in spinal nerve ligature model of neuropathic pain in rats. Additionally, microinjection of GSK189254 (a histamine H 3 receptor antagonist) into the LC reduced the evoked firing of wide dynamic range neurons in the spinal cord [32]. Although the distribution of histamine H 2 receptors in the ACC has not been reported, positron emission tomography (PET) revealed that cingulate cortex has a high density of histamine H 1 receptors [33].…”

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

“…Another two H3R antagonists, namely GSK-189254 and GSK-239512, have been described as potent, selective, and highly brain penetrant antagonists with proven effectiveness in a number of animal experiments, including attentional and memory models (Figure 10, Table 1) [53,59,[91][92][93][94][95][96][97]. Interestingly, GSK-239512 has completed phase 1 clinical trial, and the results suggest a modest efficacy in mild-moderate AD patients (ClinicalTrials.gov trial registration number: NCT00675090).…”