title: GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT7 receptor activation in rats suffering from neuropathic pain.
abstract: Among receptors mediating serotonin actions in pain control, the 5-HT(7)R 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-HT(7)R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT(7)R 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-HT(7)R 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-HT(7)R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT(7)R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT(7)R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved.
authors: INSERM U894, Neuropsychopharmacology, Centre de Psychiatrie et Neurosciences, 91 Boulevard de l'Hôpital, 75634 Paris Cedex 13, France. florentviguier@gmail.com
authors: Florent
authors: F
authors: Viguier
authors: Benoît
authors: B
authors: Michot
authors: Valérie
authors: V
authors: Kayser
authors: Jean-François
authors: JF
authors: Bernard
authors: José-Miguel
authors: JM
authors: Vela
authors: Michel
authors: M
authors: Hamon
authors: Sylvie
authors: S
authors: Bourgoin
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D006930:Hyperalgesia / Q000188:drug therapy*; D007101:Immersion / Q000503:physiopathology; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011312:Pressure; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011985:Receptors, Serotonin / Q000187:drug effects*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000473:pathology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012881:Skin Temperature / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D016760:Proto-Oncogene Proteins c-fos; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D005680:gamma-Aminobutyric Acid