Impairment in pain perception in adult rats treated with N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) as neonates

Abstract

To examine the impact of a central noradrenergic lesion on antinociceptive effects of morphine, paracetamol and nefopam, we compared intact male rats with rats in which noradrenergic nerve terminals were largely destroyed with the neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; 50 mg/kg, sc ×2] shortly after birth, on the 1st and 3rd day of postnatal life. When the rats attained 10 weeks of age, painful reactions were assessed by means of the tail immersion test (thermal stimulus) and the paw pressure test (mechanical stimulus). In addition, monoamine levels in some parts of the brain were estimated using the high pressure liquid chromatography with electrochemical detection (HPLC/ED) method. In the tail immersion test, we showed that there were no differences in the antinociceptive effect evoked by morphine (5.0 mg/kg, sc) and paracetamol (100 mg/kg, ip) between control and DSP-4 rats. Nefopam (20 mg/kg, ip) elicited only slight analgesia in control rats (~17%), and this effect was not observed in the DSP-4 treated group; differences were statistically significant at 90 and 120 min of this test. In the paw pressure test we demonstrated that morphine produced lower analgesia in DSP-4 rats in comparison to the control, and the effect was significant at 60, 90 and 120 min of the test. The antinociceptive effect of paracetamol was also greatly diminished in the DSP-4 group and significant in all tested intervals. Nefopam produced only slight analgesia in both tested groups. In biochemical studies we showed that in DSP-4 treated rats there was a marked decrease in NA level in the prefrontal cortex (to 10.4%, p < 0.005), the thalamus with the hypothalamus (to 54.4%, p < 0.005) and the spinal cord (to 12.3%, p < 0.005) in comparison to the control group. Conversely, in the cerebellum and brain stem of rats with DSP-4 lesions there was a significant increase in the NA content vs. control (to 171.2% and 123.5% of NA, respectively, with p < 0.005 and p < 0.05, respectively). In the striatum we did not observe any changes in NA level between the examined groups. The levels of 5-HT and its metabolite 5-HIAA were also not altered by DSP-4 treatment in all tested structures with the exception of the spinal cord (approx. 40% decrease) and the level of DOPAC (also 40% reduction). In conclusion, obtained results showed that neonatal DSP-4 treatment alters the antinociceptive effects of tested drugs (each of them with a different mechanism of action). These data lead to the proposal that perhaps there is a need to adjust the doses of analgesics applied to patients with noradrenergic system dysfunction (e.g., depression and/or anxiety disorders).