| Abstract No.: | A-D1126 |
| Country: | Canada |
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| Title: | THE NALOXONE-INSENSITIVE ANALGESIC EFFECTS OF PD149163 ARE BLOCKED IN NTS1 KNOCKOUT MICE |
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| Authors/Affiliations: | 1 Geneviève Roussy*; 1 Hélène Beaudry; 1 Mylène Lafrance; 1 Karine Belleville; 2 Keigi Wada; 1 Philippe Sarret;
1 Université de Sherbrooke, QC, Canada; 2 National Institute of Neuroscience, Tokyo, Japan |
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| Content: | We have recently demonstrated that NTS1 receptors participate in the analgesic effects of neurotensin at the spinal level. Indeed, centrally-injected NTS1-preferring agonists, NT69L and PD149163, produce dose-dependent antinociception in acute and tonic pain model in rodent. In the present study, we sought to investigate whether the NTS1-selective agonist, PD149163, induced antinociceptive responses in the formalin test in mice lacking the NTS1 receptor and whether PD149163-induced analgesia was opioid-dependent. To this end, we first examined the effect of intrathecal (i.t.) administration of PD149163 in NTS1 deficient, heterozygous and wild-type mice. PD149163 at a dose of 10 µg/kg induced significant antinociception in wild-type and heterozygous mice, decreasing tonic pain up to 23% and 18%, respectively. However, knockdown of NTS1 completely abolished PD149163-induced inhibition of formalin-evoked nociceptive behaviors, indicating that PD149163 effects were selectively NTS1-mediated. To determine whether the analgesic effects of PD149163 were exerted through activation of opioid-dependent pathways, mice were therefore treated with the non-selective opioid antagonist naloxone (1 mg/kg) injected intraperitoneally 15 min before i.t. administration of PD149163 (10 µg/kg). This treatment strategy failed to block PD149163-induced antinociception, demonstrating the absence of involvement of opioid receptors in the development of NTS1-mediated analgesia. These data demonstrate clearly that NTS1 receptors play an important role in the regulation of spinal nociceptive inputs and that NTS1 agonists, inducing non-opioid analgesia, may offer new avenues for the treatment of persistent and chronic pain.
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