Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

What is it about?

Neuropathic pain mechanisms are still poorly understood. In this paper we found a new molecular target, hydroxyl carboxylic acid receptor type 2 (HCAR2), that could be involved in the main symptoms associated with neuropathic pain. This target is stimulated by endogenous ketone body beta-hydroxybutyrate, which is produced after prolonged starvation and/or ketogenic diet. In particular, ketogenic diet is used to treat drug resistant epilepsy. Epilepsy and neuropathic pain have such similar profile in term of abnormal neuronal activity. Several anticonvulsant drugs are also used for treating some neuropathic pain forms (i.e. Carbamazepine for trigeminal neuralgia, pregabalin for post-herpetic neuralgia). Due to these matching mechanisms we attempted to investigate the possible involvement of beta-hydroxybutyrate and its target in the neuropathic pain symptoms. We also have used as a pharmacological approach the oral treatment with dymethilfumarate an already approved drug for the relapsing-remitting multiple sclerosis, that seems to act also on the HCAR2. The DMF has been used only as pharmacological approach to investigate the possible HCAR2-mediated effect. This study pave the way for investigation new target and new molecules in the complex neuropathic pain pathophysiology.

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Why is it important?

Our findings show for the first time the role of HCAR2 receptors in neuropathic pain pathophysiology. We highlighted that the ketone body beta-hydroxybutyrate reduced the tactile allodynia that represents the main symptom associated with neuropathic pain. Moreover, diet regimen that increases the level of beta-hydroxybutyrate, for example prolonged starvation reduced the allodynia and this effect was lost in the HCAR2 null mice

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