Comorbid anxiety-like behavior and locus coeruleus impairment in diabetic peripheral neuropathy: A comparative study with the chronic constriction injury model

Abstract

Anxiety frequently appears in patients with diabetic neuropathic pain, a highly prevalent clinical condition. However, the neurobiological mechanisms of this comorbidity are poorly known. Anxiogenic phenotype has been associated with alterations of the noradrenergic locus coeruleus (LC) after peripheral nerve entrapment. We have examined the sensorial (pain) and affective (anxiety) behaviors, and the LC activity in streptozotocin (STZ)-induced diabetic rats. A comparative study with the chronic constriction injury (CCI) model of sciatic nerve was also carried out.Diabetic nociceptive hypersensitivity was observed to appear gradually, reaching their maximum at fourth week. In contrast, CCI displayed a sharp decrease in their sensorial threshold at seventh day. In both models, anxiety-like phenotype was evident after four weeks but not earlier, coincident with the LC alterations. Indeed, STZ animals showed reduced LC firing activity, tyrosine hydroxylase, pCREB and noradrenaline transporter levels, contrary to observed in CCI animals. However, in both models, enhanced LC alpha2-adrenoceptor sensitivity was presented at this time point.This study demonstrated that diabetes induced anxiety-like behavior comorbid with LC impairment at long-term. However, the nociceptive sensitivity time-course, as well as the LC functions, showed distinct features compared to the CCI model, indicating that specific neuroplastic mechanisms are at play in every model.