Second messengers mediating high-molecular-weight hyaluronan-induced antihyperalgesia in rats with chemotherapy-induced peripheral neuropathy.

Abstract

ABSTRACT:

High-molecular-weight hyaluronan (HMWH) is an agonist at cluster of differentiation (CD)44, the cognate hyaluronan receptor, on nociceptors, where it acts to induce antihyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments, we studied the CD44 second messengers that mediate HMWH-induced attenuation of pain associated with oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN). While HMWH attenuated CIPN only in male rats, after ovariectomy or intrathecal administration of an oligodeoxynucleotide (ODN) antisense to G protein-coupled estrogen receptor (GPR30) mRNA, female rats were also sensitive to HMWH. Intrathecal administration of an ODN antisense to CD44 mRNA markedly attenuated HMWH-induced antihyperalgesia in male rats with CIPN induced by oxaliplatin or paclitaxel. Intradermal administration of inhibitors of CD44 second messengers, RhoA (member of the Rho family of GTPases), phospholipase C, and phosphatidylinositol (PI) 3-kinase gamma (PI3Kγ), attenuated HMWH-induced antihyperalgesia as does intrathecal administration of an ODN antisense to PI3Kγ. Our results demonstrated that HMWH induced antihyperalgesia in CIPN, mediated by its action at CD44 and downstream signaling by RhoA, phospholipase C, and PI3Kγ.

• Authors: Ivan J M Bonet, Larissa Staurengo-Ferrari, Dionéia Araldi, Paul G Green, Jon D Levine
• Journal: Pain (Pain) Vol. 163 Issue 9 Pg. 1728-1739 (09 01 2022) ISSN: 1872-6623 [Electronic] United States
• PMID: 34913881 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 International Association for the Study of Pain.

Chemical References

• Antineoplastic Agents
• RNA, Messenger
• Receptors, G-Protein-Coupled
• Oxaliplatin
• Hyaluronic Acid
• Type C Phospholipases
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Female
• Hyaluronic Acid (pharmacology)
• Hyperalgesia (chemically induced, drug therapy, genetics)
• Male
• Neuralgia (chemically induced)
• Oxaliplatin (adverse effects)
• Paclitaxel (adverse effects)
• RNA, Messenger
• Rats
• Receptors, G-Protein-Coupled (metabolism)
• Second Messenger Systems
• Type C Phospholipases (metabolism)