Evoked hypoalgesia is accompanied by tonic pain and immune cell infiltration in the dorsal root ganglia at late stages of diabetic neuropathy in mice

Abstract

Diabetic peripheral neuropathy is a major debilitating late complication of diabetes, which significantly reduces the quality of life in patients. Diabetic peripheral neuropathy is associated with a wide spectrum of sensory abnormalities, where in loss of sensation or hypoalgesia to applied external stimuli is paradoxically accompanied by debilitating tonic spontaneous pain. In numerous studies on animal models of diabetic peripheral neuropathy, behavioural measurements have been largely confined to analysis of evoked withdrawal to mechanical and thermal stimuli applied to dermatomes, whereas spontaneous, on-going pain has not been widely studied. In the Streptozotocin model of type 1 diabetes, we employed the Conditioned Place Preference test to assess tonic pain. Our results indicate that both phases, that is, early evoked hypersensitivity (i.e. 5–7 weeks post-Streptozotocin) as well as late stage hypoalgesia (i.e. 17–20 weeks post-Streptozotocin) are accompanied by significant tonic pain in mice with diabetic peripheral neuropathy. We also report on the temporal relation between on-going pain and neuropathological changes in the dorsal root ganglia of mice with diabetic peripheral neuropathy up to 6 months post-Streptozotocin. Neither early hypersensitivity nor late hypoalgesia were associated with markers of cellular stress in the dorsal root ganglia. Whereas significant neutrophil infiltration was observed in the dorsal root ganglia over both early and late stages post-Streptozotocin, T-cell infiltration in the dorsal root ganglia was prominent at late stages post-Streptozotocin. Thus, longitudinal analyses reveal that similar to patients with chronic diabetic peripheral neuropathy, mice show tonic pain despite sensory loss after several months in the Streptozotocin model, which is accompanied by neuroimmune interactions in the dorsal root ganglia.

Putative roles of SLC7A5 (LAT1) transporter in pain

“…The role of T-cells in chronic neuropathic and inflammatory pain states is an area of active research ( Laumet et al, 2019 ). T-cells contribute to the generation and maintenance of neuropathic pain by infiltrating into the nervous system days to weeks post-nerve injury ( Moalem et al, 2004 , Agarwal et al, 2018 ). First, they infiltrate the site of injury and the spinal nerve, then the DRG, and finally the SDH ( Moalem et al, 2004 ).…”

A TLR–CXCL1 pathway in DRG neurons induces neutrophil accumulation in the DRG and mechanical allodynia in EAE mice

“…Based on the data that neutrophil-depleted mice did not show mechanical allodynia, it is evident that neutrophils certainly play an important role in the generation of mechanical allodynia during the preclinical phase of EAE. Naïve mice never show mechanical allodynia under physiological condition, although neutrophils are located in the DRG 37 . Distinct from previous data, we could not observe MPO/NE immunoreactivity in the DRG of sham mice.…”

Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice

“…Several studies have used rodent models to evaluate hypoalgesia. Thermal hypoalgesia in rodents has been observed in the late stage of STZ-induced type I diabetic models [ 47 , 51 , 58 , 59 , 60 , 61 , 62 ] and in various type II diabetic models, including the HFD-induced diabetic model and db/db mice [ 63 , 64 , 65 ]. Here, we confirmed the paradoxical alteration of pain perception, such as hyperalgesia and hypoalgesia/hypoesthesia in the type II HFD- or db/db model and type I STZ-model.…”

“…Here, we confirmed the paradoxical alteration of pain perception, such as hyperalgesia and hypoalgesia/hypoesthesia in the type II HFD- or db/db model and type I STZ-model. Notably, many studies revealed that hyperalgesia occurs at the early stage after STZ-treatment(s), and hypoalgesia does several weeks later, though the timing showing the transition from hyperalgesia to hypoalgesia depends on the experimental models [ 47 , 51 , 58 , 61 , 62 ]. In the present study, we observed significant thermal hyperalgesia in HFD-, db/db- and STZ-models, but failed to detect the thermal hypoalgesia by the time of 10 weeks after the start of HFD-treatments, or 49 days (7 weeks) after STZ-treatment.…”