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J Pharmacol Exp Ther. 2019 Sep 3. pii: jpet.119.261339. doi: 10.1124/jpet.119.261339. [Epub ahead of print]

Streptozotocin-induced diabetic neuropathic pain is associated with potentiated calcium-permeable AMPA receptor activity in the spinal cord.

Author information

1
MD Anderson Cancer Center.
2
University of Texas M. D. Anderson Cancer Center huilinpan@mdanderson.org.

Abstract

Neuronal hyperactivity in the spinal dorsal horn can amplify nociceptive input in diabetic neuropathic pain. The glutamate N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDA receptors and AMPA receptors, respectively) are involved in spinal nociceptive transmission. However, it is unclear whether painful diabetic neuropathy is associated with changes in the activity of synaptic NMDA receptors and AMPA receptors in spinal dorsal horn neurons. AMPA receptors lacking GluA2 are Ca2+ permeable (CP-AMPA receptors), and their currents display characteristic inward rectification. In this study, we showed that evoked excitatory postsynaptic currents (EPSCs) exhibited inward rectification in spinal dorsal neurons in diabetic rats induced by streptozotocin. Interestingly, presynaptic and postsynaptic NMDA receptor activity in the spinal dorsal horn was similar in diabetic and control rats. In the dorsal spinal cord, the membrane GluA2 protein level was significantly less in diabetic than in control rats, whereas the cytosolic GluA2 level was greater in diabetic than in control rats. In contrast, the GluA1 subunit levels in the plasma membrane and cytosol did not differ between the two groups. Blocking CP-AMPA receptors significantly reduced the amplitude of EPSCs of dorsal horn neurons in diabetic but not in control rats. Furthermore, blocking spinal CP-AMPA receptors reduced pain hypersensitivity in diabetic rats but had no effect on nociception in control rats. Our study suggests that diabetic neuropathy augments CP-AMPA receptor activity in the spinal dorsal horn by causing intracellular retention of GluA2 and impairing GluA2 membrane trafficking. Increased prevalence of spinal CP-AMPA receptors sustains diabetic neuropathic pain. SIGNIFICANCE STATEMENT: This study demonstrates that the prevalence of synaptic calcium permeable-AMPA receptors is increased in the spinal dorsal horn, which mediates pain hypersensitivity in diabetic neuropathy. Thus, calcium permeable-AMPA receptors play an important role in glutamatergic synaptic plasticity in the spinal cord in painful diabetic neuropathy. This new knowledge improves our understanding of the mechanisms involved in central sensitization associated with diabetic neuropathic pain and suggest that calcium permeable-AMPA receptors are an alternative therapeutic target for treating this chronic pain condition.

KEYWORDS:

glutamate; neuropathic pain; neurotransmitters

PMID:
31481518
DOI:
10.1124/jpet.119.261339
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