Activation of NK₁ receptors in the locus coeruleus induces analgesia through noradrenergic‐mediated descending inhibition in a rat model of neuropathic pain

Article

Author: Suzuki, H. ; Muto, Y. ; Sakai, A. ; Sakamoto, A.

BACKGROUND AND PURPOSEThe locus coeruleus (LC) is a major source of noradrenergic projections to the dorsal spinal cord, and thereby plays an important role in the modulation of nociceptive information. The LC receives inputs from substance P (SP)‐containing fibres from other regions, and expresses the NK1 tachykinin receptor, a functional receptor for SP. In the present study, we investigated the roles of SP in the LC in neuropathic pain.EXPERIMENTAL APPROACHChronic constriction injury (CCI) of the left sciatic nerve was performed in rats to induce neuropathic pain. After development of neuropathic pain, SP was injected into the LC and the nocifensive behaviours were assessed. The involvement of noradrenergic descending inhibition in SP‐induced analgesia was examined by i.t. administration of yohimbine, an α2‐adrenoceptor antagonist. NK1 receptor expression in the LC was examined by immunohistochemistry.KEY RESULTSIn CCI rats, mechanical allodynia was alleviated by SP injection into the LC. These effects were abolished by prior injection of WIN 51708, an NK1 receptor antagonist, into the LC or i.t. treatment with yohimbine. NK1 receptor‐like immunoreactivity was observed in noradrenergic neurons throughout the LC in intact rats, and remained unchanged after CCI.CONCLUSION AND IMPLICATIONSSP in the LC exerted analgesic effects on neuropathic pain through NK1 receptor activation and resulted in facilitation of spinal noradrenergic transmission. Accordingly, manipulation of the SP/NK1 receptor signalling pathway in the LC may be a promising strategy for effective treatment of neuropathic pain.

08 Mar 2012·Journal of Medicinal ChemistryQ1 · MEDICINE

Fluorescent Derivatives of AC-42 To Probe Bitopic Orthosteric/Allosteric Binding Mechanisms on Muscarinic M1 Receptors

Q1 · MEDICINE

Article

Author: Daval, Sandrine B. ; Galzi, Jean-Luc ; Bonnet, Dominique ; Kellenberger, Esther ; Valant, Céline ; Hibert, Marcel ; Ilien, Brigitte

Two fluorescent derivatives of the M1 muscarinic selective agonist AC-42 were synthesized by coupling the lissamine rhodamine B fluorophore (in ortho and para positions) to AC42-NH(2). This precursor, prepared according to an original seven-step procedure, was included in the study together with the LRB fluorophore (alone or linked to an alkyl chain). All these compounds are antagonists, but examination of their ability to inhibit or modulate orthosteric [(3)H]NMS binding revealed that para-LRB-AC42 shared several properties with AC-42. Carefully designed experiments allowed para-LRB-AC42 to be used as a FRET tracer on EGFP-fused M1 receptors. Under equilibrium binding conditions, orthosteric ligands, AC-42, and the allosteric modulator gallamine behaved as competitors of para-LRB-AC42 binding whereas other allosteric compounds such as WIN 51,708 and N-desmethylclozapine were noncompetitive inhibitors. Finally, molecular modeling studies focused on putative orthosteric/allosteric bitopic poses for AC-42 and para-LRB-AC42 in a 3D model of the human M1 receptor.

01 Jan 2012·Journal of Nippon Medical SchoolQ4 · MEDICINE

Involvement of Tachykinins and NK<sub>1</sub> Receptor in the Joint Inflammation with Collagen Type II-Specific Monoclonal Antibody-Induced Arthritis in Mice

Q4 · MEDICINE

Article

Author: Sakai, Atsushi ; Makino, Akira ; Suzuki, Hidenori ; Ito, Hiromoto

Rheumatoid arthritis (RA) is a chronic multisystem disease characterized by persistent joint inflammation associated with severe pain. Because RA is an immune-mediated joint disease and because type II collagen is considered an autoantigen, rodent models of arthritis using collagen type II-specific monoclonal antibodies are valuable for studying the pathogenesis of autoimmune arthritis and for evaluating therapeutic strategies. The tachykinin family peptides, substance P (SP) and hemokinin-1 (HK-1), are expressed in the nervous systems and in many peripheral organs and immunocompetent cells and activate tachykinin NK1 receptors with similar affinities. NK1 receptors are involved in the inflammation and hyperalgesia associated with a variety of inflammatory diseases. In the present study, we examined the involvement of SP and HK-1 in the joint inflammation and hyperalgesia in a collagen antibody-induced arthritis (CAIA) model in mice. The messenger RNA expression levels of the TAC1 gene encoding SP and of the TAC4 gene encoding HK-1 were decreased in the dorsal root ganglia and spinal cord at the peak of the inflammatory symptoms in CAIA. Systemic injection of an NK1 receptor antagonist, WIN 51708, significantly inhibited the joint swelling, but not the mechanical allodynia, on day 7 in CAIA mice. The messenger RNA expression levels of TAC1 and TAC4 in the dorsal root ganglia and dorsal spinal cord were unaffected by treatment with WIN 51708. These findings suggest that tachykinins and NK1 receptors play a key role in joint inflammation, rather than in nociceptive sensitization, in CAIA.

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Indication	Highest Phase	Country/Location	Organization	Date
Pain	Discovery	GB	Sterling Winthrop Group Ltd	-

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