incb3344 and Neuralgia

Prostaglandin (PG) E

Topics: Animals; Cells, Cultured; Chemokine CCL2; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Pain Measurement; Pyrrolidines; Receptors, CCR2; Receptors, Prostaglandin E, EP3 Subtype; Sciatic Nerve

Chemokine (C-C motif) ligand 2 (CCL2) participates in different mechanisms contributing to the spinal cord inflammation and pain development after sciatic nerve injury. Recent data also support its role in orofacial thermal hypersensitivity, although its implication in different phases of trigeminal pain emergence is unclear. We assessed the importance of CCL2 signalling in biochemical and behavioural alterations during the early and late stages following chronic constriction injury of infraorbital nerve (ION-CCI), a model of peripheral traumatic trigeminal pain.. After evaluating the consequences of CCL2 intracisternal injection in naïve rats, we determined the expression changes for CCL2, inflammatory and glia activation markers in the somatosensory trigeminal complex (STC) and trigeminal ganglia (TG) after ION-CCI. The role of CCL2 signalling was assessed using pre-emptive or 'curative' intracisternal treatment with specific CCL2 receptor antagonist - INCB3344.. Exogenous CCL2 evoked spontaneous behaviour reminiscent of orofacial pain and marked mechanical hypersensitivity, associated with increased expression of proinflammatory cytokines and glial markers in STC and TG. CCL2-evoked changes were prevented by the co-administration of INCB3344. Two weeks after ION-CCI, mRNA for CCL2, glial and inflammatory markers were up-regulated, and CCL2-immunoreactivity accumulated in central and ganglionic tissues. At this time, repeated intracisternal administration of INCB3344 did not attenuate the ION-CCI-associated behavioural nor biochemical changes. By contrast, pre-emptive INCB3344 treatment delayed the emergence of trigeminal mechanical allodynia and associated biochemical alterations.. Our data suggest that CCL2 is involved principally in the early events accompanying the ION lesion rather than in long-term alterations and the maintenance of trigeminal mechanical hypersensitivity.

Topics: Animals; Chemokine CCL2; Facial Pain; Hyperalgesia; Male; Neuralgia; Nociception; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, CCR2; Signal Transduction; Trigeminal Ganglion

CCL2 chemokine and its receptor CCR2 may contribute to neuropathic pain development. We tested the hypothesis that injury to peripheral nerves triggers CCL2 release from afferents in the dorsal horn spinal cord (DHSC), leading to pronociceptive effects, involving the production of proinflammatory factors, in particular. Consistent with the release of CCL2 from primary afferents, electron microscopy showed the CCL2 immunoreactivity in glomerular boutons and secretory vesicles in the DHSC of naive rats. Through the ex vivo superfusion of DHSC slices, we demonstrated that the rate of CCL2 secretion was much lower in neonatal capsaicin-treated rats than in controls. Thus, much of the CCL2 released in the DHSC originates from nociceptive fibers bearing TRPV1 (transient receptor potential vanilloid 1). In contrast, high levels of CCL2 released from the DHSC were observed in neuropathic pain animal model induced by chronic constriction of the sciatic nerve (SN-CCI). The upregulated expression of proinflammatory markers and extracellular signal-regulated kinase (ERK) 1/2 pathway activation (ERK1/2 phosphorylation) in the DHSC of SN-CCI animals were reversed by intrathecal administration of the CCR2 antagonist INCB3344 (N-[2-[[(3S,4S)-1-E4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxy-3-pyrrolidinyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide). These pathological pain-associated changes in the DHSC were mimicked by the intrathecal injection of exogenous CCL2 in naive rats and were prevented by the administration of INCB3344 or ERK inhibitor (PD98059). Finally, mechanical allodynia, which was fully developed 2 weeks after SN-CCI in rats, was attenuated by the intrathecal injection of INCB3344. Our data demonstrate that CCL2 has the typical characteristics of a neuronal mediator involved in nociceptive signal processing and that antagonists of its receptor are promising agents from treating neuropathic pain.

Topics: Animals; Animals, Newborn; Blotting, Western; Chemokine CCL2; Chronic Disease; Constriction, Pathologic; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases; Fluorescent Antibody Technique; Hyperalgesia; Immunohistochemistry; Inflammation; Male; Microscopy, Electron; Neuralgia; Neurons; Peripheral Nerve Injuries; Protein Kinase Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, CCR2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sciatic Nerve; Spinal Cord; Synaptic Vesicles