Effect of DSP4 and desipramine in the sensorial and affective component of neuropathic pain in rats

Abstract

Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2weeks after injury by administering the antidepressant desipramine (10mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independently.

Keywords: Acetone (PubChem CID: 180); Affective component of pain; Anterior cingulate cortex; Antidepressant; Chloral hydrate (PubChem CID: 270); DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride]; DSP4, [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (PubChem CID: 3172); Desipramine (PubChem CID: 2995); Ketamine Hydrochloride (PubChem CID:15851); Neuropathic pain; Sensory component of pain; Sodium chloride (PubChem CID: 5234); Xylazine: (PubChem CID: 5707).