Increased α2δ-1-NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy-induced neuropathic pain

Painful peripheral neuropathy is a severe and difficult-to-treat neurological complication associated with cancer chemotherapy. Although chemotherapeutic drugs such as paclitaxel are known to cause tonic activation of presynaptic NMDA receptors (NMDARs) to potentiate nociceptive input, the molecular mechanism involved in this effect is unclear. alpha 2 delta-1, commonly known as a voltage-activated calcium channel subunit, is a newly discovered NMDAR-interacting protein and plays a critical role in NMDAR-mediated synaptic plasticity. Here we show that paclitaxel treatment in rats increases the alpha 2 delta-1 expression level in the dorsal root ganglion and spinal cord and the mRNA levels of GluN1, GluN2A, and GluN2B in the spinal cord. Paclitaxel treatment also potentiates the alpha 2 delta-1-NMDAR interaction and synaptic trafficking in the spinal cord. Strikingly, inhibiting alpha 2 delta-1 trafficking with pregabalin, disrupting the alpha 2 delta-1-NMDAR interaction with an alpha 2 delta-1 C-terminus-interfering peptide, or alpha 2 delta-1 genetic ablation fully reverses paclitaxel treatment-induced presynaptic NMDAR-mediated glutamate release from primary afferent terminals to spinal dorsal horn neurons. In addition, intrathecal injection of pregabalin or alpha 2 delta-1 C-terminus-interfering peptide and alpha 2 delta-1 knockout in mice markedly attenuate paclitaxel-induced pain hypersensitivity. Our findings indicate that alpha 2 delta-1 is required for paclitaxel-induced tonic activation of presynaptic NMDARs at the spinal cord level. Targeting alpha 2 delta-1-bound NMDARs, not the physiological alpha 2 delta-1-free NMDARs, may be a new strategy for treating chemotherapy-induced neuropathic pain. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at .