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Diabetic peripheral neuropathy (DPN) is a major debilitating late complication of diabetes, which significantly reduces the quality of life in patients. DPN 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 DPN, 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 (STZ) model of type 1 diabetes, we employed the Conditioned Place Preference (CPP) test to assess tonic pain. Our results indicate that both phases, i.e. early evoked hypersensitivity (i.e. 5-7 weeks (wks) post-STZ) as well as late stage hypoalgesia (i.e. 17-20 wks post-STZ) are accompanied by significant tonic pain in mice with DPN. We also report on the temporal relation between on-going pain and neuropathological changes in the dorsal root ganglia (DRG) of mice with DPN up to 6 months post-STZ. Neither early hypersensitivity nor late hypoalgesia were associated with markers of cellular stress in the DRG. Whereas significant neutrophil infiltration was observed in the DRG over both early and late stages post-STZ, T-cell infiltration in the DRG was prominent at late stages post-STZ. Thus, longitudinal analyses reveal that similar to patients with chronic DPN, mice show tonic pain despite sensory loss after several months in the STZ model, which is accompanied by neuroimmune interactions in the dorsal root ganglia.

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