Detection of calcium-associated nociceptive activity in neuropathic pain models using [51Mn]MnCl2 PET/MR

Abstract

Calcium influx is a fundamental component of neuronal signaling and is markedly altered during neuropathic pain. Voltage-gated calcium channels (VGCCs) play a central role in nociceptive transmission; however, multiple calcium-permeable pathways contribute to calcium-associated neural activity. Because Mn 2+ shares similar ionic properties and cellular transport mechanisms with Ca 2+ , positron-emitting [ 51 Mn]MnCl 2 has potential as a molecular imaging probe for visualizing pain-associated calcium activity in vivo. This study evaluated [ 51 Mn]MnCl 2 PET/MR for detecting neuropathic pain-associated neural activity in a rat spared nerve injury (SNI) model before and after analgesic intervention. Male Sprague–Dawley rats underwent SNI surgery or sham surgery and were evaluated using von Frey behavioral testing, in vivo [ 51 Mn]MnCl 2 PET/MR imaging, before and after sustained-release buprenorphine administration. Ex vivo biodistribution was completed after all imaging studies were completed. Tracer uptake within the spinal cord and peripheral nervous system was compared between SNI and sham animals. SNI animals demonstrated significantly increased mechanical hypersensitivity accompanied by elevated [ 51 Mn]MnCl 2 uptake within the spinal cord regions associated with sciatic nerve innervation before analgesic intervention. Following buprenorphine administration, behavioral hypersensitivity and spinal cord tracer uptake were reduced, while ex vivo biodistribution demonstrated significantly greater tracer accumulation within injured sciatic nerves compared to sham controls. These findings provide proof-of-concept evidence that positron-emitting manganese can detect neuropathic pain-associated calcium-related neural activity in the SNI model. While additional studies are needed to establish mechanistic specificity, improve quantitative assessment of peripheral nerves, and validate findings in larger cohorts, [ 51 Mn]MnCl 2 PET/MR shows promise as a molecular imaging approach for investigating neuropathic pain.