• The Korean Journal of Pain
• /
• v.35 no.2
• /
• pp.173-182
• /
• 2022

Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

• Korean Journal of Veterinary Research
• /
• v.43 no.3
• /
• pp.405-414
• /
• 2003

The purpose of this study was to assess the role of tachykinins (TK) in mediating nonadrenergic noncholinergic (NANC) contractions produced by electrical field stimulation (EFS) in the longitudinal muscle of the rat ileum. In the presence of atropine ($1{\mu}M$), guanethidine ($5{\mu}M$), and L-nitroarginine (L-NNA, $200{\mu}M$), EFS (0.5ms pulse duration, 120 V, 1-20 Hz for 2 min) produced a frequency-dependent slowly-developing tonic contraction with superimposed phasic contractions ('on'-contraction) followed by off slowly-decreasing tonic and superimposed phasic contractions ('off'-contraction) of mucosa-free longitudinal oriented muscle strip. These EFS induced responses were blocked by tetrotoxin. $NK_1$ receptor selective antagonist L-732,138 strongly inhibited the EFS-induced excitatory responses. However $NK_2$ receptor selective antagonist, GR 159897 and $NK_3$ receptor selective antagonist SB 222200 did not significantly inhibited the responses. $NK_1$ receptor selective agonist [$Sar^9$,$Met(O_2)^{11}$] Substance P and $NK_2$ receptor selective agonist [${\beta}-Ala^8$]-neurokinin A (4-10) induced tonic contraction with superimposed phasic contractions of longitudinal oriented muscle strip and almost blocked by selective antagonist L-732,138 and GR 159897, respectively. But $NK_3$ receptor selective agonist senktide did not showed any effect. Nifedipine ($1{\mu}M$) abolished the contraction produced either by EFS or by the TK receptor agonists [$Sar^9$,$Met(O_2)^{11}$] Substance P or [${\beta}-Ala^8$]-neurokinin A (4-10). It is concluded that, in the longitudinal muscle of rat ileum, both $NK_1$ and $NK_2$ receptors modulated the responses to exogenous tachykinins, whereas $NK_1$ is mainly involved in NANC neuromuscular contraction.

• Journal of Radiopharmaceuticals and Molecular Probes
• /
• v.5 no.2
• /
• pp.158-162
• /
• 2019

[¹¹C]GR205171, a Neurokinin 1 (NK1) radioligand, has been known as such a promising PET probe for quantitation of NK1 receptors in the brain by positron emission tomography (PET) imaging. First trial to synthesis of [¹¹C]GR205171 was to use methylene chloride and tetrabutylammonium hydroxide for preactivation of precursor, but the result was not successful in radiochemical yield (0~25%) and unreliable. 7 years later, inorganic base (Cs₂CO₃) was tried to achieve higher radiochemical yield, and they showed higher yield (~53%). We have tried to repeat the same synthesis method, but it did not work properly, because there were the lack of the detail procedure and still reproducibility in radiochemical yield. Here we report the improved synthesis protocol to produce [¹¹C]GR205171 in high yield via commercial automated synthesizer. The sonicator which combines water heating bath was used to activate desmethyl-GR205171, and this method showed high efficiency and reasonable yields (4.7 ± 0.6%, non-decay corrected from molecular sieve trap) with >95% radiochemical purity.

• YAKHAK HOEJI
• /
• v.41 no.1
• /
• pp.139-146
• /
• 1997

In the present study, capsaicin-induced desensitization of peripheral sensory nerves were investigated by using guinea pig bronchi, in which these nerves are stimulated with cap saicin to produce a contractile response via the release of sensory neuropeptides such as substance P and neurokinin A. The contractile response to capsaicin was inhibited by the combination of CP96345 and SR 48968 suggesting that the excitatory effect of capsaicin is mediated via both the tachykinin NK-1 and NK-2 receptor. Capsaicin produced in vitro-desensitization in dose-dependent manner, but after this in vitro-desensitization the response to NK-1 and NK-2 receptor agonist did not change. Systemic administration (s.c.) of capsaicin also desensitized significantly bronchial tissues but could not produce any change in the contractile response to the selective agonists of NK-1 and NK-2 receptor. Therefore, the present results suggest that functional desensitization to capsaicin-induced contractile response in guinea pig bronchi does not involve NK-1 and NK-2 receptor, while excitatory effect of capsaicin is mediated via both NK-1 and NK-2 receptor. In conclusion, it is suggested that capsaicin- induced excitation and desensitization involves somewhat different pathways.

• Journal of Korean Neurosurgical Society
• /
• v.42 no.6
• /
• pp.462-469
• /
• 2007

Objective : This study characterized the neurons in the lumbosacral cord that express phospho ERK (pERK) after distension or irritation of the bladder, and their relation to the vanilloid receptor 1 (VR1) positive primary afferents. Methods : Mechanical distension and chemical irritation of the bladder were induced by intravesical injection of the saline and mustard oil, respectively. Spinal neurons expressing pERK and the primary afferent fibers were characterized using multiple immunofluorescence for neurokinin 1 (NK1), neuronal nitric oxide synthetase (nNOS) and VR1. Results : Neurons in lamina I, medial dorsal horn (MDH), dorsal gray commissure (DGC) and sacral parasympathetic nucleus (SPN) were immunoreactive for pERK after either mechanical or chemical stimulation. The majority of pERK positive cells were positive for NK1 in lamina I and SPN, but not in the DGC. Most of pERK positive cells are not stained for nNOS except in a small population of the cells in the SPN and DGC. Contacts between perikarya and dendrites of pERK-positive cells and terminals of primary afferents expressing VR1 were identified in lamina I. lateral collateral path (LCP) and SPN. Conclusion : In this study, the lumbosacral neurons activated by mechanical and chemical stimulation of the urinary bladder were identified with expression of the pERK, and also provided the evidence that VR1-positive primary afferents may mediate the activation of these neurons.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.22
• /
• pp.9587-9592
• /
• 2014

Nausea and vomiting are common adverse events in chemotherapy. In spite of the serious effects on the quality of life and further treatment, they remain overlooked by physicians, and no standard treatment has been developed. Neurokinin-1 (NK-1) receptor antagonists and palonosetron are the major agents in the standard regimen for treating moderately and highly emetogenic chemotherapy-induced nausea and vomiting (CINV). However, NK-1 receptor antagonists first became commercially available at the end of 2013 and palonosetron has not been extensively applied in China. Olanzapine was recommended as a therapy for moderate and severe CINV in antiemesis-clinical practice guidelines in oncology in 2014 for the first time. It is an atypical antipsychotic agent, which can block multiple receptors on neurotransmitters. During more than 10 years, olanzapine has demonstrated significant effects in preventing CINV and treating breakthrough and refractor CINV, which was observed in case reports, precise retrospective studies, and phase I, II and III clinical trials, with no grade 3 to 4 adverse events. In particular, it is superior to aprepitant and dexamethasone in delayed nausea and vomiting. Therefore, this compound is worthy of further investigation.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1996.04a
• /
• pp.252-252
• /
• 1996

We Investigated the peripheral excitatory effect of capsaicin and KR-25018, a newly synthesized capsaicin derivative which was demonstrated to have a potent analgesic activity. KR-25018 and capsaicin were found to be both potent efficacious contractors of isolated guinea pig bronchial smooth muscle. KR-25018 was equipotent with capsaicin and [Sar$\^$9/,Met(O$_2$)$\^$11/]-substance P, 10-fold more potent than histamine and 10-fold less potent than (${\beta}$ -Ala$\^$8/)-neurokinin A(4-10), and their -log(M)EC$\_$50/ values were 6.94${\pm}$0.08, 6.86${\pm}$0.05, 6.96${\pm}$0.07, 5.64${\pm}$0.04, 7.96${\pm}$0.02, respectively. Contractile responses to KR-25018 and capsaicin were potentiated by phosphoramidon (1 ${\mu}$M), an inhibitor of neuropeptide-inactivating endopeptidase, but completely abolished in a calcium-free medium. These responses to KR-25018 and capsaicin were unaffected by the NK-1 antagonist CP96345 (1${\mu}$M), partially inhibited by the NK-2 antagonist SR48968 (1 ${\mu}$M) but almost completely abolished by a combination of the antagonists. A vanilloid receptor antagonist capsazepine competitively antagonized the responses to both KR-25018 and capsaicin (pA$_2$: aganst KR-25018, 5.98${\pm}$0.47; against capsaicin, 5.80${\pm}$0.31), and a capsaicin-sensitive cation channel antagonist ruthenium red caused significant reduction in the maximum responses to KR-25018 and capsaicin (pD'$_2$: against KR-25018, 4.61${\pm}$0.33; against capsaicin 4.96${\pm}$0.21). In conclusion, the present results suggest that KR-25018 and cpasaicin act on the same vanilloid receptor inducing the influx of calcium through ruthenium red-sensitive cation channel and produce contractile responses via the release of tachykinins that act on both NK-1 and NK-2 receptor subtypes.

• BMB Reports
• /
• v.29 no.5
• /
• pp.429-435
• /
• 1996

To investigate the structure-antagonistic relationship of the cyclohexapeptide L-659,877, a selective NK-2 tachykinin receptor antagonist, seven analogues were chemically synthesized by a solid phase method. The agonistic and antagonistic activities of the analogues were evaluated by contraction assay using the smooth muscle of guinea pig trachea (GPT) containing the NK-2 receptor. It was shown that the aromatic ring of Phe at position 3 and the sulfur group of Met at position 6 in L-659,877 were essential for binding to the NK-2 receptor. Decrease in antagonistic activity of L-659,877 caused by substituting Leu for Nle at position 5 indicates that the ${\gamma}$ methyl group and side chain length of Leu plays an important role in its antagonistic action. Although the activity was slightly lower than L-659,877, cyclo $[{\beta}Ala^{8}]NKA(4-10)$ (analogue 1) showed potential antagonistic activity for the NK-2 receptor. It was confirmed that the expansion of the ring in L-659,877 by substitution of ${\beta}Ala$ for Gly at position 4 stabilized its conformation monitored by CD spectra. The results suggest that analogue 1 can be used as a new leader compound to design a more powerful, selective, and stable NK-2 receptor antagonist.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.22
• /
• pp.9627-9630
• /
• 2014

Background: Although efficacy of aprepitant for suppressing emesis associated with single-dose cisplatin has been demonstrated, there are limited data on the antiemetic effect of this oral neurokinin-1 receptor antagonist during daily administration of cisplatin. Accordingly, we investigated the efficacy and safety of aprepitant in patients with head and neck cancer (HNC) receiving combination therapy with cisplatin and 5-FU (FP therapy). Materials and Methods: Twenty patients with HNC were prospectively studied who received a triple antiemetic regimen comprising granisetron ($40{\mu}g/kg$ on Days 1-4), dexamethasone (8 mg on Days 1-4), and aprepitant (125 mg on day 1 and 80mg on days 2-5) with FP therapy (cisplatin $20mg/m^2$ on days 1-4; 5-FU $400mg/m^2$ on days 1-5) (aprepitant group). We also retrospectively studied another 20 HNC patients who received the same regimen except for aprepitant (control group). Results: For efficacy endpoints based on nausea, the aprepitant group showed significantly better results, including a higher rate of complete response (no vomiting and no salvage therapy) for the acute phase (p=0.0342), although there was no marked difference between the two groups with regard to percentage of patients in whom vomiting was suppressed. There were no clinically relevant adverse reactions to aprepitant. Conclusions: This study suggested that a triple antiemetic regimen containing aprepitant is safe and effective for HNC patients receiving daily cisplatin therapy.

• Korean Journal of Clinical Pharmacy
• /
• v.20 no.1
• /
• pp.17-23
• /
• 2010

Aprepitant is a substance P/neurokinin-1 (NK1)-receptor antagonist that was approved in 2003 for prevention of CINV. In addition, updated anti-emetic guidelines that include the aprepitant regimen have been published by NCCN and ASCO. However there is scarce clinical data in Korea. The prospective study was performed to evaluate the prevention of high dose cisplatin induced nausea and vomiting in all patients who started high-dose cisplatin-based chemotherapy at our hospital. We checked the nausea severity and vomiting episodes by calling patients within 4 to 5 days after chemotherapy. The retrospective study was performed to compare the prevention of CINV in solid tumor patients who switched their anti-emesis regimen from the standard regimen to the aprepitant regimen. In aprepitant regimen, aprepitant was added to the same anti-emetic regimen used during previous cycles. We checked the nausea, vomiting grades and adverse events in electronic medical records (EMR). In prospective study, 195 patients were included in the analysis. 88.2% of patients achieved a complete response (no emesis and no rescue therapy). In retrospective study, 54 patients were reviewed. With aprepitant regimen, nausea and vomiting grades were improved in 22 patients (40.7%) and in 9 patients (16.7%), respectively. Compared with standard regimen, addition of aprepitant provided superior prevention against CINV in Korean patients receiving highly emetogenic cisplatin-based chemotherapy. Moreover, aprepitant significantly prevented CINV in patients who received the standard regimen to prevent CINV in previous chemotherapy cycles.