UC San Diego

Background

Chemotherapeutic agents, such as cisplatin, are known to induce a persistent polyneuropathy. The mechanisms underlying the development of this pain are complex, and have only been investigated rodent models using male animals, despite an equivalent presentation of neuropathy between the sexes, clinically.

Methods

Male and female C57Bl/6, Tlr3(-/-) Tlr4(-/-) , Myd88(-/-) , Trif(lps2) and Myd88(-/-) /Trif(lps2) mice received 6 i.p. injections of cisplatin (2.3 mg/kg/day) every other day over the course of 2 weeks. Changes in tactile threshold were monitored during this time, continuing through day 23, using von Frey filaments.

Results

Male WT mice develop a persistent tactile allodynia resulting from cisplatin administration. Female mice develop an initial allodynia, but thresholds return to baseline by day 23. Deletion of TLR3, TLR4, MyD88 and Trif/MyD88 protects animals from the development of cisplatin-induced polyneuropathy, and there are no sex differences. Trif(lps2) male mice show a persistent tactile allodynia following cisplatin administration, while female mice show a reduced allodynia, and remain higher in threshold than their male counterparts. On day 18, animals were given the analgesic gabapentin, and thresholds were tested 45 min after. Gabapentin was effective in transiently reversing mechanical allodynia in those mice with lowered thresholds.

Conclusions

It is important to continue examining both sexes in various pain models, as a mononeuropathy and polyneuropathy show sex differences in pain development and the role of TLR signalling.