Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog.

Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog. Eur J Pharmacol. 2020 Jun 10;:173174 Authors: Tétreault P, Besserer-Offroy É, Brouillette RL, René A, Murza A, Fanelli R, Kirby K, Parent AJ, Dubuc I, Beaudet N, Côté J, Longpré JM, Martinez J, Cavelier F, Sarret P Abstract 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 Pro10 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 antinocic...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharmacol Source Type: research