GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT7 receptor activation in rats suffering from neuropathic pain

Among receptors mediating serotonin actions in pain control, the 5-HT7R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT7R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT7R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT7R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1ß mRNA overexpression in ipsilateral L4–L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN-associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 μg i.t.), but neither phaclofen (5 μg i.t.) nor naloxone (10 μg i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT7R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT7R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT7R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved. ► 5-HT7 receptor agonists reduced mechanical hyperalgesia in sciatic nerve-ligated rats. ► Intrathecal bicuculline blocked 5-HT7R-mediated antihyperalgesia in neuropathic rats. ► 5-HT7R-mediated antihyperalgesia is unaffected by spinal opioid receptors blockade. ► Both spinal and supraspinal processes contributed to 5-HT7R-mediated antihyperalgesia.