NTS2-selective analogs as an alternative treatment to chronic pain

Chronic pain is a major health problem affecting 20% of the world population. Consequently, this medical condition represents an enormous burden on the quality of life and mental health of affected patients, not to mention the astronomical cost to the economy and healthcare systems. Mild analgesics such as non-steroidal anti-inflammatory drugs, acetaminophen or antidepressant drugs often have limited efficacy for moderate to severe pain. On the other hand, opioids remain among the strongest analgesics available, despite the serious physiological effects associated with opioid therapy such as respiratory depression and constipation. Moreover, long-term opioid therapy can lead to addiction and tolerance, further increasing the incidence of adverse effects. The aim of this project was to develop safer analgesics that are independent of the opioidergic system. The neurotensinergic system has emerged as an interesting candidate for this purpose. Indeed, neurotensin (NT) receptors NTS1 and NTS2 are highly expressed in regions involved in pain control and have demonstrated strong analgesic properties in vivo. Activation of NTS1 is also associated with other physiological effects, including modulation of body temperature, blood pressure, and cancer, which are not desired for the treatment of chronic pain. Thus, this master’s project focused on the development of neurotensin (NT) analogs selective for the NTS2 receptor, which is not associated with NTS1-mediated secondary effects. First, a series of peptide analogs was synthesized with different modifications to NT(8-13) peptide to improve its pharmacological properties as well as selectivity for NTS2. Next, plasma stability and affinity for NT receptors were assessed in vitro for each analog. Analogs with the most interesting pharmacological profile were tested for analgesic potential using different animal pain models such as model of acute thermal pain, tonic inflammatory pain, chronic inflammatory pain, and chronic neuropathic pain. Changes in body temperature and blood pressure were monitored to verify if these analogs are associated with NTS1-mediated effects. Finally, because there is a well-established sex difference in pain symptoms and analgesic response, the candidate which demonstrated the best results in vivo was tested for analgesic efficacy in females with chronic pain to assess whether a gender difference exists with this NT(8-13) analog.

Name thesis:degree_name

M. Sc.

Level thesis:degree_level

Maîtrise

Discipline thesis:degree_discipline

Pharmacologie

Grantor dc:publisher

Université de Sherbrooke

Year dc:date.issued

2022

Author dc:creator

• Beaulieu, Sabrina

Advisor dc:contributor.advisor

• Sarret, Philippe

• Neurotensin
• NTS2
• Neurotensin analog
• Chronic pain
• Analgesia
• Neurotensine
• Analogue neurotensinergique
• Douleur chronique
• Analgésie

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/11143/19497

OAI identifier oai:identifier

oai:usherbrooke.scholaris.ca:11143/19497