Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain

Abstract

Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP.

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

“…The aim of this study was to determine the region-specific behavioral and electrophysiological effects of mGlu5 receptor blockade with caged and photoswitchable NAMs in neuropathic pain using photopharmacology. While the effect of optical manipulations of photosensitive mGlu5 NAMs in individual brain regions in pain models has been studied before ( 12, 13, 32 ), the comparative analysis across different brain regions and their contribution to systemically applied NAMs represents a novel concept.…”

“…Photopharmacological approaches have recently been explored for pain modulation by members of our team (12)(13)(14) and by others (15,16). The drug treatment of neuropathic pain, i.e., chronic pain originating from damage or disease of the somatosensory system, remains a major therapeutic challenge and unmet medical need because of severe side effects and a high percentage of patients resistant to medication (17,18).…”

“…The use of photoactive drugs also allows an extremely rapid control of pain, circumventing the anatomical barrier that limits the access of analgesic agents to their target sites. For example, light-induced activation of JF-NP-26 in the thalamus caused rapid and robust analgesia in a mouse model of breakthrough cancer pain, a sudden severe, and transient type of pain that may develop in cancer patients under treatment with opioids ( 13 ). Light-activation of JF-NP-26 can help identify the site within the pain neuraxis where mGlu5 receptor blockade is sufficient to cause analgesia.…”

Breakthrough pain among cancer patients at oncology units in Northern Ethiopia; a multi-center study

“…Breakthrough pain is frequent in cancer patients and is often characterized by a rapid onset, short duration, and severe intensity ( 5 , 40 ). In this study, the prevalence of breakthrough cancer pain was 41.5% and it was consistent with previous studies that reported 39.3% ( 41 ), 41% ( 42 ), and 40.3% ( 43 ).…”