vuf-8430 and Neuralgia

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

Neuropathic pain is under-treated, with a detrimental effect on quality of life, partly because of low treatment efficacy, but also because pathophysiological mechanisms are not fully elucidated. To clarify the pathobiology of neuropathic pain, we studied the contribution of neuroinflammation and oxidative stress in a model of peripheral neuropathy. We also assessed an innovative treatment for neuropathic pain by investigating the effects of histamine H. A peripheral mononeuropathy was induced in mice, by spared nerve injury (SNI). Neuroinflammation and oxidative stress parameters were evaluated by spectrophotometry. The mechanical (von Frey test) and thermal (plantar test) nociceptive thresholds were evaluated.. SNI mice showed increased expression of the pro-inflammatory cytokines IL-1ß and TNF-α, decreased antioxidant enzyme Mn-containing SOD (MnSOD), increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, and of PARP, nuclear enzyme activated upon DNA damage. Intrathecal administration of VUF 8430 (H. In the SNI mouse model of neuropathic pain, neuronal H

Topics: Animals; Dose-Response Relationship, Drug; Guanidines; Histamine; Inflammation; Male; Mice; Neuralgia; Oxidative Stress; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Spinal Cord Injuries; Structure-Activity Relationship; Thiourea

Histamine is a chemical mediator that acts at four known types of histamine receptors and has been widely implicated in the development of nociception and neuropathic pain. Blocking histamine H(1) and H(2) receptors has been shown to reduce hyperalgesia following nerve injury, but the role of histamine H(3) and H(4) receptors in neuropathic pain has not been studied. Here, we used blockers of histamine H(3) and H(4) receptors to assess their effects on neuropathic pain behavior and mast cell numbers following peripheral nerve injury. In addition, we assessed the effect of activating H(4) receptors on neuropathic pain behavior.. Rats were subjected to a partial ligation of the sciatic nerve, a model of neuropathic pain, and were treated either systemically or locally (hindpaw) with the H(3)/H(4) receptor inverse agonist thioperamide, the specific H(4) receptor antagonist JNJ 7777120, or the H(4) receptor agonist VUF 8430. Measurements of mechanical hyperalgesia were carried out by Randall-Selitto test for 1-3 weeks, and sciatic nerve tissues were analyzed for numbers of intact mast cells by histology at 9 h after surgery.. Rats treated with thioperamide or JNJ 7777120 showed significantly enhanced mechanical hyperalgesia after partial ligation of the sciatic nerve. The number of intact mast cells in the injured nerve of these rats was higher than in control rats suggesting reduced mast cell degranulation, but was still significantly lower than in intact nerves. Rats treated with VUF 8430 showed significantly reduced mechanical hyperalgesia.. We propose that the increase in mechanical hyperalgesia produced by thioperamide and JNJ 7777120 and the decrease in mechanical hyperalgesia produced by VUF 8430 may represent a direct effect of these agents on mechanospecific primary afferents, or an indirect effect of these agents via injury-induced inflammation.

Topics: Animals; Guanidines; Histamine Antagonists; Hyperalgesia; Indoles; Ligation; Male; Mast Cells; Neuralgia; Pain Threshold; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Sciatic Nerve; Thiourea