Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glial activation and central sensitization. At 4 weeks after tibia fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (L-2-aminoadipic acid (LAA)) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglial and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 h after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglial activation after limb fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS.

2015-09-01·Experimental Neurology2区 · 医学

Intranigral administration of substance P receptor antagonist attenuated levodopa-induced dyskinesia in a rat model of Parkinson's disease

2区 · 医学

Article

作者: Cui, Guiyun ; Zhao, Hui ; Shi, Hongjuan ; Wang, Xiaoying ; Hua, Fang ; Zu, Jie ; Yang, Xinxin ; Zhang, Zunsheng ; Zhang, Shenyang ; Zhang, Wei ; Shen, Xia

Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6-hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of γ-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity-regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa.

2014-10-29·Investigative Ophthalmology & Visual Science2区 · 医学

NK1 Receptor Antagonists as a New Treatment for Corneal Neovascularization

2区 · 医学

ArticleOA

作者: Lorusso, Anna ; Rama, Paolo ; Aramini, Andrea ; Ferrari, Giulio ; Giacomini, Chiara ; Bignami, Fabio

PURPOSETo determine whether the inhibition of Substance P (SP) activity can reduce corneal neovascularization (CNV) by means of local administration of high-affinity, competitive, tachykinin 1 receptor (NK1R) antagonists Lanepitant and Befetupitant.METHODSWe performed a safety and efficacy study by using (1) two different C57BL/6 mouse models of CNV: alkali burn and sutures; (2) different concentrations; and (3) different routes of administration: topical or subconjunctival. Clinical examination endpoints, SP levels, CNV index, and leukocyte infiltration were measured.RESULTSSubstance P increased after injury in the corneal epithelium of both CNV models, and later in the suture model. Topical Lanepitant was nontoxic to the ocular surface and effective in reducing hemangiogenesis and lymphangiogenesis, corneal SP levels, and leukocyte infiltration, as soon as 4 days later in the alkali burn model. Topical Lanepitant, up to 7 days, was ineffective in the suture model. However, subconjunctival Lanepitant was effective in reducing lymphatic CNV, leukocyte infiltration, and SP levels in the suture model, after 10 days. Additionally, in the alkali burn model, subconjunctival Lanepitant significantly reduced blood CNV, corneal perforation rate, opacity, and leukocyte infiltration, and improved tear secretion. Finally, topical application of Befetupitant reduced CNV in the alkali burn model but was toxic owing to the vehicle (dimethyl sulfoxide [DMSO]); hence, Befetupitant was not tested in the suture model.CONCLUSIONSThe NK1R antagonist Lanepitant is safe for the ocular surface and effective in reducing both corneal hemangiogenesis and lymphangiogenesis, and leukocyte infiltration. We suggest that inhibition of NK1R may represent an adjunctive tool in the treatment of CNV.

100 项与拉奈匹坦相关的药物交易

登录后查看更多信息