期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 882, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2020.173174
关键词
Unnatural aminoacid; Antinociception; Constipation; Tolerance; Formalin; neuropathic
资金
- Canadian Institutes for Health Research (CIHR) [MFE-135472]
- Fond de recherche du Quebec - Sante (FRQ-S) [255989]
- CIHR [MFE-164740]
- FRQ-S
- Faculty of Medicine and Health Sciences of the Universite de Sherbrooke Ph.D. scholarships
- Tier 1 Canada Research Chair in Neurophysiopharmacology of Chronic Pain
- FRQ-S-funded Quebec Pain Research Network (QPRN)
- National Institute of Mental Health (NIMH), Chemical Synthesis and Drug Supply Program [PD149163]
Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS1 and NTS2 receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro(10) residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS1 activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS1 and NTS2, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, repeated agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据