Background and Purpose Misuse of opioids has greatly affected our society. One potential solution is to develop analgesics that act at targets other than opioid receptors. These can be used either as stand‐alone therapeutics or to improve the safety profile of opioid drugs. Previous research showed that activation of Gq/11 proteins by G‐protein coupled receptors has pro‐nociceptive properties, suggesting that blockade of Gq/11 signalling could be beneficial for pain control. The aim of this study was to test this hypothesis pharmacologically by using potent and selective Gq/11 inhibitor YM‐254890. Experimental Approach We used a series of behavioural assays to evaluate the acute responses of mice to painful thermal stimulation while administering YM‐254890 alone and in combination with morphine. We then used electrophysiological recordings to evaluate the effects of YM‐254890 on the excitability of dorsal root ganglion (DRG) nociceptor neurons. Key Results We found that systemic administration of YM‐254890 produced anti‐nociceptive effects and also augmented morphine analgesia in both hotplate and tail flick paradigms. However, it also caused substantial inhibition of locomotion, which may limit its therapeutic utility. To circumvent these issues, we explored the local administration of YM‐254890. Intrathecal injections of YM‐254890 produced lasting analgesia in a tail flick test and greatly augmented the anti‐nociceptive effects of morphine without any significant effects on locomotor behaviour. Electrophysiological studies showed that YM‐254890 reduced the excitability of DRG nociceptors and augmented their opioid‐induced inhibition. Conclusion and Implications These findings indicate that pharmacological inhibition of Gq/11 could be explored as an analgesic strategy.

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