Time-shifted co-administration of sub-analgesic doses of ambroxol and pregabalin attenuates oxaliplatin-induced cold allodynia in mice

Background: Oxaliplatin-induced cold allodynia is a frequent complication appearing in patients treated with this anti-tumor drug. Since, there are no clear algorithms to overcome this painful condition effectively, it is important to establish novel strategies for its treatment. Aim: In this study, the ability of pregabalin and ambroxol, used as single drugs or in combinations administered in a time-shifted manner to attenuate cold allodynia was assessed in the mouse cold plate test. The hot plate test was additionally used to assess antinociceptive properties of ambroxol in the acute, thermally-induced pain model. Locomotor activity and motor coordination of mice were also evaluated. In silico studies were undertaken to predict potential binding of ambroxol to sodium channel (Nay) subtypes whose overexpression is implicated in the development of oxaliplatin-induced neuropathic pain. Key findings: A hyperadditive antiallodynic effect of combined sub-analgesic ambroxol and pregabalin was demonstrated in oxaliplatin-treated mice. This effect was particularly strong when these drugs were given 4 h apart. Both drugs used in combination reduced animals' locomotor activity, but they did not impair motor coordination in the rotarod test. Ambroxol did not show antinociceptive properties in the hot plate test. The molecular docking studies predicted that in mice ambroxol might bind to Na(y)1.6 and Na(y)1.9 rather than Na(y)1.7 and Na(y)1.8. Significance: Time-shifted co-administration of sub-analgesic doses of ambroxol and pregabalin effectively attenuates oxaliplatin-induced cold allodynia. Molecular docking model predicts preferential binding of ambroxol to mouse Na(y)1.6, Na(y)1.9 channels. This mechanism, if confirmed in vitro, might explain pharmacological activities observed in vivo.