Pathological pain processing in mouse models of multiple sclerosis and spinal cord injury: contribution of plasma membrane calcium ATPase 2 (PMCA2)

Abstract

BackgroundNeuropathic pain is often observed in individuals with multiple sclerosis (MS) and spinal cord injury (SCI) and is not adequately alleviated by current pharmacotherapies. A better understanding of underlying mechanisms could facilitate the discovery of novel targets for therapeutic interventions. We previously reported that decreased plasma membrane calcium ATPase 2 (PMCA2) expression in the dorsal horn (DH) of healthy PMCA2+/− mice is paralleled by increased sensitivity to evoked nociceptive pain. These studies suggested that PMCA2, a calcium extrusion pump expressed in spinal cord neurons, plays a role in pain mechanisms. However, the contribution of PMCA2 to neuropathic pain processing remains undefined. The present studies investigated the role of PMCA2 in neuropathic pain processing in the DH of wild-type mice affected by experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and following SCI.MethodsEAE was induced in female and male C57Bl/6N mice via inoculation with myelin oligodendrocyte glycoprotein fragment 35–55 (MOG35–55) emulsified in Complete Freund’s Adjuvant (CFA). CFA-inoculated mice were used as controls. A severe SC contusion injury was induced at thoracic (T8) level in female C57Bl/6N mice. Pain was evaluated by the Hargreaves and von Frey filament tests. PMCA2 levels in the lumbar DH were analyzed by Western blotting. The effectors that decrease PMCA2 expression were identified in SC neuronal cultures.ResultsIncreased pain in EAE and SCI was paralleled by a significant decrease in PMCA2 levels in the DH. In contrast, PMCA2 levels remained unaltered in the DH of mice with EAE that manifested motor deficits but not increased pain. Interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and IL-6 expression were robustly increased in the DH of mice with EAE manifesting pain, whereas these cytokines showed a modest increase or no change in mice with EAE in the absence of pain. Only IL-1β decreased PMCA2 levels in pure SC neuronal cultures through direct actions.ConclusionsPMCA2 is a contributor to neuropathic pain mechanisms in the DH. A decrease in PMCA2 in DH neurons is paralleled by increased pain sensitivity, most likely through perturbations in calcium signaling. Interleukin-1β is one of the effectors that downregulates PMCA2 by acting directly on neurons.

Prolonged Analgesia by Spinal Cord Stimulation Following a Spinal Injury Associated With Activation of Adult Neural Progenitors

“…L4-6, some distance below the SCI lesion at T13, numerous reports, [30][31][32] and indeed Figure 2, clearly demonstrate hindlimb reflex mechanical hypersensitivity following thoracic SCI. Similarly, the reversal of this SCI-induced hypersensitivity by SCS at T12 clearly has a profound analgesic impact on sensory processing at L4-6.…”

“…It is of course not clear that these specific parameters could be usefully extrapolated into a clinical context. While inputs from the plantar hindlimb reach the spinal cord at segments L4–6, some distance below the SCI lesion at T13, numerous reports, 30–32 and indeed Figure 2, clearly demonstrate hindlimb reflex mechanical hypersensitivity following thoracic SCI. Similarly, the reversal of this SCI‐induced hypersensitivity by SCS at T12 clearly has a profound analgesic impact on sensory processing at L4–6.…”

Disturbed Presynaptic Ca2+ Signaling in Photoreceptors in the EAE Mouse Model of Multiple Sclerosis

“…Therefore, we also assume that the decreased immunosignal in the OPL of MOG/CFA-injected mice obtained with the anti-PMCA2/3 antibody is mainly caused by a decrease in the synaptic expression of PMCA2. Of particular interest, PMCA2 was previously found to be altered in the spinal cord in the EAE mouse model of MS and responsible for early neuronal dysfunction ( Nicot et al., 2003 , 2005 ; Kurnellas et al., 2007 ; Mirabelli et al., 2019 ). Furthermore, PMCA2/3 was the only protein that we found to be reduced in western blot analyses ( Figures 11 , S11 , and S12 ), indicating that PMCA2 could play a prominent role in the synaptic pathology in early EAE.…”

Cytokine Profile as a Marker of Cell Damage and Immune Dysfunction after Spinal Cord Injury

“…These findings suggest that various structural synaptic changes in the spinal cord and hippocampal neurons are mediated by the overproduction of TNF-α in activated microglial cells, which can be associated with the development of chronic neuropathic pain and memory deficit after spinal cord injury [142]. IL-1β reducing the efficiency of calcium pump function in neurons also contributes to the development of neuropathic pain [143].…”