Calcineurin inhibitors, such as
tacrolimus (
FK506) and
cyclosporine, are widely used as standard
immunosuppressants in
organ transplantation recipients. However, these drugs can cause severe
pain in patients, commonly referred to as
calcineurin inhibitor-induced
pain syndrome (CIPS). Although
calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of
FK506 in male and female mice significantly increased the amount of α2δ-1-GluN1 complexes in the spinal cord and the level of α2δ-1-bound GluN1
proteins in spinal synaptosomes. Treatment with
FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2δ-1 with
gabapentin or disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat
peptide completely reversed the effects of
FK506. In α2δ-1 gene KO mice, treatment with
FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of
gabapentin or
intrathecal injection of α2δ-1Tat
peptide reversed thermal and mechanical
hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2δ-1 genetic KO similarly attenuated FK506-induced thermal and mechanical
hypersensitivity. Together, our findings indicate that α2δ-1-bound NMDARs mediate
calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.SIGNIFICANCE STATEMENT
Calcineurin inhibitors are
immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained
pain. We showed that
calcineurin inhibition enhances physical interaction between α2δ-1 and NMDARs and their synaptic trafficking in the spinal cord. α2δ-1 is essential for
calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2δ-1 or disrupting α2δ-1-NMDAR interaction reduces
calcineurin inhibitor-induced
pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2δ-1 KO also attenuates
calcineurin inhibitor-induced
pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous
calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.