Over the past decades, accumulating evidence has demonstrated a pivotal role of cholecystokinin type 2 receptor (CCK2R) in pain modulation. The established role of CCK2R activation in directly facilitating nociception has led to the development of several CCK2R antagonists, which have been shown to successfully alleviate pain in several rodent models of pain. However, the outcomes of clinical trials are more modest since they have not demonstrated the expected biological effect obtained in animals. Such discordances of results between preclinical and clinical studies suggest reconsidering our knowledge about the molecular basis of the pharmacology and functioning of CCK2R. This review focuses on the cellular localization of CCK2R specifically in the sensory nervous system and discusses in further detail the molecular mechanisms and signal transduction pathways involved in controlling pain perception. We then provide a comprehensive overview of the most successful compounds targeting CCK2R and report recent advances in pharmacological strategies used to achieve CCK2R modulation. We purposely distinguish between CCK2R benefits obtained in preclinical models and outcomes in clinical trials with different pain etiologies. Lastly, we emphasize the biological and clinical relevance of CCK2R as a promising target for the development of new treatments for pain management.
Vincristine (VCR) is responsible for the onset of the VCR-induced peripheral neuropathy (VIPN), associated with neuropathic pain. Several reports have strongly linked the cholecystokinin type 2 receptor (CCK2R) to nociceptive modulation. Thus, our aim was to evaluate the effect of CCK2R blockade on the onset of VIPN, as well as its interaction on VCR anticancer efficacy. VCR was administrated in mice for 8 days (100 µg/kg/d, i.p.). Transcriptomic analysis of the dorsal root ganglia (DRG) was performed at day 7 in VCR and control mice. Proglumide (30 mg/kg/d), a CCK1R and CCK2R antagonist, and Ly225910 (1 mg/kg/d), a selective CCK2R antagonist, were administrated one day before and during VCR treatment. Tactile sensitivity was assessed during treatments. Immunofluorescence and morphological analyses were performed on the skin, DRG and sciatic nerve at day 7. The cytotoxicity of VCR in combination with proglumide/Ly225910 was evaluated in human cancer cell lines. Cck2r was highly upregulated in the DRG of VCR mice. Proglumide accelerated the recovery of normal sensitivity, while Ly225910 totally prevented the onset of allodynia and nerve injuries induced by VCR. Proglumide or Ly225910 in combination with VCR did not affect the cytotoxicity of VCR. Targeting CCK2R could therefore be an effective strategy to prevent the onset of VIPN.
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