RESUMO
BACKGROUND: Current pain management is limited, in particular, with regard to chronic pain. In an attempt to discover novel analgesics, we combined the approach developed to characterize traditional Chinese medicine (TCM), as part of the "herbalome" project, with the reverse pharmacology approach aimed at discovering new endogenous transmitters and hormones. RESULTS: In a plant used for centuries for its analgesic properties, we identify a compound, dehydrocorybulbine (DHCB), that is effective at alleviating thermally induced acute pain. We synthesize DHCB and show that it displays moderate dopamine receptor antagonist activities. By using selective pharmacological compounds and dopamine receptor knockout (KO) mice, we show that DHCB antinociceptive effect is primarily due to its interaction with D2 receptors, at least at low doses. We further show that DHCB is effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance. CONCLUSIONS: Our study casts DHCB as a different type of analgesic compound and as a promising lead in pain management.
Assuntos
Alcaloides/farmacologia , Analgésicos/farmacologia , Corydalis/química , Isoquinolinas/farmacologia , Medicina Tradicional Chinesa , Dor/tratamento farmacológico , Alcaloides/química , Alcaloides/isolamento & purificação , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Células HEK293 , Humanos , Inflamação/complicações , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Masculino , Camundongos , Dor/etiologiaRESUMO
Neuropeptides control a wide spectrum of physiological functions. They are central to our understanding of brain functions. They exert their actions by interacting with specific G protein-coupled receptors. We however have not found all the neuropeptides that exist in organisms. The search for novel neuropeptides is thus of great interest as it will lead to a better understanding of brain function and disorders. In this review, we will discuss the historical as well as the current approaches to neuropeptide discovery, with a particular emphasis on the orphan GPCR-based strategies. We will also discuss two novel peptides, neuropeptide S and neuromedin S, as examples of the impact of neuropeptide discovery on our understanding of brain functions. Finally, the challenges facing neuropeptide discovery will be discussed.
