Sexual dimorphism in the nociceptive effects of hyaluronan.

Intradermal administration of low molecular weight hyaluronan (LMWH) in the hindpaw induced dose-dependent (0.1, 1, or 10 µg) mechanical hyperalgesia, of similar magnitude in male and female rats. However, the duration of LMWH hyperalgesia was greater in females. This sexual dimorphism was eliminated by bilateral ovariectomy, and by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to the G-protein-coupled estrogen receptor (GPR30) mRNA, in females, indicating estrogen dependence. To assess the receptors at which LMWH acts to induce hyperalgesia, LMWH was administered to groups of male and female rats that had been pretreated with ODN antisense (or mismatch) to the mRNA for one of three hyaluronan receptors, cluster of differentiation 44 (CD44), toll-like receptor 4 (TLR4) or receptor for HA-mediated motility (RHAMM). While LMWH-induced hyperalgesia was attenuated in both male and female rats pretreated with ODN antisense for CD44 and TLR4 mRNA, RHAMM antisense pretreatment only attenuated LMWH-induced hyperalgesia in males. ODN antisense for RHAMM, however, attenuated LMWH-induced hyperalgesia in female rats treated with ODN antisense to GPR30, as well as in ovariectomized females. LMWH-induced hyperalgesia was significantly attenuated by pretreatment with high molecular weight hyaluronan (HMWH) in male, but not in female rats. Following gonadectomy or treatment with ODN antisense to GPR30 expression in females, HMWH produced similar attenuation of LMWH-induced hyperalgesia to that seen in males. These experiments identify nociceptors at which LMWH acts to produce mechanical hyperalgesia, establishes estrogen dependence in the role of RHAMM in female rats, and establishes estrogen-dependence in the inhibition of LMWH-induced hyperalgesia by HMWH.