Differential adaptive changes on serotonin and noradrenaline transporters in a rat model of peripheral neuropathic pain

Abstract

Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathicpain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenalinetransporters (5-HTT and NAT) in aratmodel of neuropathicpain, the spinal nerve ligation (SNL). Quantitative autoradiography revealed a significant decrease in the density of 5-HTT ([3H]citalopram binding) at the level of the lumbar spinal cord following 2 weeks of neuropathic surgery (lamina V, −40%: 6.01 ± 0.64 nCi/mg tissue in sham-animals vs 3.59 ± 1.56 in SNL-animals; lamina X, −30%: 9.10 ± 2.00 vs 6.40 ± 1.93 and lamina IX, −22%: 12.01 ± 2.41 vs 9.42 ± 1.58). By contrast, NAT density ([3H]nisoxetine binding) was significantly increased (lamina I–II, +34%: 2.20 ± 0.45 vs 2.96 ± 0.65; lamina V, +57%: 1.34 ± 0.28 vs 2.11 ± 0.66; and lamina IX, +58%: 2.39 ± 0.71 vs 3.78 ± 1.10). At supraspinal structures, SNL induced adaptivechanges only in the density of 5-HTT (septal nuclei, +33%: 10.18 ± 2.03 vs 13.53 ± 1.14; CA3 field of hippocampus, +18%: 6.94 ± 1.01 vs 8.21 ± 0.81; paraventricular thalamic nucleus, +21%: 15.18 ± 1.88 vs 18.35 ± 2.08; lateral hypothalamic area, +40%: 12.68 ± 1.90 vs 17.8 ± 2.55; ventromedial hypothalamic nuclei, +19%: 7.16 ± 0.92 vs 8.55 ± 0.40; and dorsal raphe nucleus, +15%: 35.22 ± 3.88 vs 40.68 ± 3.11). Thus, we demonstrate, in the SNL model of neuropathicpain, the existence of opposite changes in the spinal expression of 5-HTT (down-regulation) and NAT (up-regulation), and the presence of supraspinal adaptivechanges (up-regulation) only on 5-HTT density. These findings may help understanding the pathogeny of neuropathicpain and the differential analgesic action of antidepressants targeting 5-HTT and/or NAT transporters.