Patients with schwannomatosis (SWN) develop multiple tumors, called schwannomas, along peripheral nerves, with most experiencing significant pain. Neuropathic, nociceptive, and inflammatory pain types have been reported, but many patients describe severe pain when a schwannoma is palpated or lightly touched. Currently, surgical removal is the only effective treatment for pain relief. We are investigating mechanisms of tumor-induced pain. In some cases, schwannoma growth increases pressure on nearby nerves, resulting in pain. Additionally, schwannoma cells in culture secrete proinflammatory cytokines into the surrounding medium (CM) that increases neuronal sensitivity both in vitro and in vivo. When injected into a mouse hind paw, painful CM reduced paw withdrawal thresholds fourfold within one hour (p = 0.006), with effects lasting 48 h (p = 0.002) as demonstrated by Von Frey assay. We developed a chronic SWN pain model showing neuronal priming by SWN CM. After priming, a secondary CM exposure prolongs mechanical hypersensitivity for up to two weeks (p < 0.0001). We hypothesize this is mediated by mechanosensitive ion channels (MSCs), which respond to pressure and stretch. GsMTx-4, a selective MSC blocker, penetrates strained membranes to prevent MSC opening without affecting other channels. When co-injected with CM into the mouse paw, 10 µM GsMTx-4 prevented hypersensitivity to light touch. Moreover, GsMTx-4 reversed hyperalgesia even in the primed state, restoring withdrawal thresholds to baseline (p < 0.0001). These findings suggest that local injection of GsMTx-4 near painful tumors offers a promising, minimally invasive therapeutic approach for SWN pain.

Pain is a confounding comorbidity in the multiple tumor syndrome schwannomatosis. Patients harbor benign peripheral nerve sheath tumors that rarely become malignant or cause neurological deficits. Yet, patients undergo numerous surgeries for the removal of painful tumors. A non-invasive treatment for tumor-related pain is in dire need. We are examining the small peptide GsMTx-4, a blocker of mechanosensitive ion channels, as a potential therapy for painful tumors in the context of schwannomatosis.