Mise en évidence du rôle physiologique de la chimiokine CCL2 dans la neurotransmission nociceptive au niveau spinal

Abstract : Contrary to popular beliefs, chronic pain is not only a set of symptoms, but a bona fide pathology that the drugs currently available are not sufficient to efficiently relieve. There is thus a need to modify our approach to discover new analgesic agents, taking into consideration the specific physiopathology of chronic pain. With this in mind, we investigated the role of chemokines and their receptors in the modulation of pain. Also known for their participation in the immune response, we focused on the CCL2-CCR2 ability to regulate arthritic pain. We first evaluated the analgesic properties of INCB3344, a specific antagonist of the CCR2 receptor, in a model of inflammatory pain. It reverses both provoked and spontaneous pain by 50% when administered i.t. We also observed that spinally blocking CCR2 limited the expression of proinflammatory mediators. It also reduced peripheral inflammation by preventing peripheral transport of SP. We then translated our findings in a model of arthritic pain, closer to the clinical reality of patients with rheumatoid arthritis. Spinal administration of INCB3344 had similar analgesic actions, but did not altered peripheral inflammation. On the other hand, peripheral administration of INCB3344, either by subcutaneous injection or by continuous release assured by an osmotic pump, had almost no analgesic effects, but significantly reduced peripheral inflammation and reduced the weight loss. By combining INCB3344 with a daily administration of ibuprofen, we were however able to reduce both pain hypersensitivity and the severity of the peripheral inflammation. Taken together, these results suggest that CCR2 antagonism has promising analgesic properties; especially for inflammatory or arthritic pain as it can acts both on the sensibilized nociceptive network and on the peripheral source of the inflammatory pain. This become even more interesting as its mechanism is at least not completely redundant with those of classic non-steroidal anti-inflammatory drugs, which allow the combination of both class of molecule to yield even larger effect.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

Doctorat

Discipline thesis:degree_discipline

Physiologie

Grantor dc:publisher

Université de Sherbrooke

Year dc:date.issued

2015

Author dc:creator

• Dansereau, Marc-André

Advisor dc:contributor.advisor

• Sarret, Philippe

• Douleur
• Douleur arthritique
• Douleur inflammatoire
• CCL2
• CCR2
• INCB3344
• Distribution pondérale dynamique
• Inflammation neurogénique
• Chimiokines
• Mini-pompes osmotiques
• Pain
• Arthritic pain
• Inflammatory pain
• Dynamic weight bearing
• Neurogenic inflammation
• Chemokines
• Osmotic mini-pump

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-nd/2.5/ca/

Language dc:language.iso

fr

Handle dc:identifier.uri

http://hdl.handle.net/11143/6069

OAI identifier oai:identifier

oai:usherbrooke.scholaris.ca:11143/6069