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

Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathic pain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenaline transporters (5-HTT and NAT) in a rat model of neuropathic pain, 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 adaptive changes 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 neuropathic pain, the existence of opposite changes in the spinal expression of 5-HTT (down-regulation) and NAT (up-regulation), and the presence of supraspinal adaptive changes (up-regulation) only on 5-HTT density. These findings may help understanding the pathogeny of neuropathic pain and the differential analgesic action of antidepressants targeting 5-HTT and/or NAT transporters.

► Spinal nerve ligation (SNL) decreased 5-HTT density in the spinal cord. ► SNL increased 5-HTT density in forebrain regions and midbrain. ► SNL only induced changes on NAT density (up-regulation) in the spinal cord.