Background & Aims

Chronic pain is a condition suffered by millions globally. Chemotherapy-induced peripheral neuropathy (CIPN) is a major type of chronic pain caused by the chemotherapeutic drugs such as oxaliplatin. The accompanied side effect of cold allodynia often leads to cessation of chemotherapy. IQ motif containing GTPase activating protein 1 (IQGAP1) has been shown to promote chronic inflammatory pain and nerve injury-induced neuropathic pain through sensitizing TRPA1 channels. TRPA1 has been implicated in noxious cold sensing and cold allodynia although it is controversial. This research aims to investigate the role of IQGAP1 in noxious cold sensing and cold allodynia in CIPN and the underlying mechanisms.

Methods

Cold plate was used to examine noxious cold sensing in wild-type (WT) and IQGAP1-deficient mice. These mice were also used to induce acute and chronic cold allodynia by intraplantar and intraperitoneal injection of oxaliplatin, respectively. Cold allodynia in the mice was then monitored using cold plate. Whole-cell patch clamp was employed to characterise electrical properties of sensory DRG neurons. Oxidative stress in DRG neurons was revealed by Western blotting and ROS-sensitive fluorescence dye. The effect of oxaliplatin on TRPA1 responses in DRG neurons were determined using Ca2+ imaging by treating DRG neurons with oxaliplatin (300µM) for 2h.

Results

Acute noxious cold sensing was significantly diminished in IQGAP1-lacking mice in response to noxious cold temperatures. Acute and chronic cold allodynia in IQGAP1-/- mice were also reduced. A similar reduction in cold allodynia was also observed in WT mice by administering the TRPA1 antagonist HC-030031. Rheobase and IKD currents were significantly increased without changes in basal TRPA1 currents in IQGAP1-deificent DRG neurons compared to WT neurons. However, oxaliplatin treatment markedly enhanced TRPA1 responses but inhibited IKD in DRG neurons. Correspondingly, inhibition of IKD with 4-AP triggered more neuronal responses in the presence of oxaliplatin. Interestingly, all these effects were prevented in IQGAP1 knockout DRG neurons. Furthermore, oxaliplatin provoked more reactive oxygen species (ROS) production in WT DRG than those in IQGAP1-knockout DRG. Consistently, cold allodynia was reduced by activating Nrf2, a transcription factor initiating antioxidant responses.

Conclusions

Our results suggest that IQGAP1 participates in noxious cold sensing through regulating IKD currents but promotes oxaliplatin-elicited cold allodynia through both TRPA1 and voltage-gated K+ channels. IQGAP1 does so likely through facilitating ROS production. IQGAP1 thus represents an alternative therapeutic target to alleviate not only pain induced by inflammation or nerve injury but also chemotherapy-induced neuropathy. [1, 2]

References

1.Khan, S., et al., IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels. Brain, 2023. 146(6): p. 2595-2611.
2.Brown, M.D. and D.B. Sacks, IQGAP1 in cellular signalling: bridging the GAP. Trends Cell Biol, 2006. 16(5): p. 242-9.

Presenting Author

Adam Campbell-Galland

Poster Authors

Adam Campbell-Galland

PhD

University of Warwick

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic