Theta-Burst Stimulation of Primary Afferents Drives Long-Term Potentiation in the Spinal Cord and Persistent Pain via a243-1-Bound NMDA Receptors

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception in male and female mice. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS triggered LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting a243-1 with gabapentin, or a243-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the a243-1-NMDAR interaction with a243-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not a243-1 knockout, mice. TBS significantly increased the a243-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or a2431Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via a243-1-dependent NMDAR activation. a2431-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury.

Automated summary

Research shows that theta-burst stimulation (TBS) has an impact on synaptic plasticity and pain in mice, inducing more long-term potentiation (LTP) in spinal cord neurons. Nerve injury increases the prevalence of TBS-induced LTP, and interventions targeting NMDARs or a243-1 can reduce TBS-induced pain hypersensitivity.