Pain(FunPep)

Facial pain in multiple sclerosis is often due to trigeminal neuralgia but atypical pictures can be observed.

A man with primary progressive multiple sclerosis developed severe unilateral facial pain in the right orbital region. Spontaneous and triggered attacks were associated with ipsilateral conjunctival injection and lacrimation. A diagnosis of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing was made, and symptoms significantly improved with lamotrigine.

Pain is poorly investigated in multiple sclerosis, with a dramatic impact on patients’ life quality. In this light, standardized evaluation of pain is needed to improve patient management.

This study introduces a novel approach for synthesizing Benzoxazine‐centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN.