Abstract
Activation of the dorsomedial nucleus of the hypothalamus (DMH) by galanin (GAL) induces behavioural hyperalgesia. Since DMH neurones do not project directly to the spinal cord, we hypothesized that the medullary dorsal reticular nucleus (DRt), a pronociceptive region projecting to the spinal dorsal horn (SDH) and/or the serotoninergic raphe-spinal pathway acting on the spinal 5-HT3 receptor (5HT3R) could relay descending nociceptive facilitation induced by GAL in the DMH. Heat-evoked paw-withdrawal latency (PWL) and activity of SDH neurones were assessed in monoarthritic (ARTH) and control (SHAM) animals after pharmacological manipulations of the DMH, DRt and spinal cord. The results showed that GAL in the DMH and glutamate in the DRt lead to behavioural hyperalgesia in both SHAM and ARTH animals, which is accompanied particularly by an increase in heat-evoked responses of wide-dynamic range neurons, a group of nociceptive SDH neurones. Facilitation of pain behaviour induced by GAL in the DMH was reversed by lidocaine in the DRt and by ondansetron, a 5HT3R antagonist, in the spinal cord. However, the hyperalgesia induced by glutamate in the DRt was not blocked by spinal ondansetron. In addition, in ARTH but not SHAM animals PWL was increased after lidocaine in the DRt and ondansetron in the spinal cord. Our data demonstrate that GAL in the DMH activates two independent descending facilitatory pathways: (i) one relays in the DRt and (ii) the other one involves 5-HT neurones acting on spinal 5HT3Rs. In experimental ARTH, the tonic pain-facilitatory action is increased in both of these descending pathways.
Highlights
Galanin (GAL) inhibits or enhances nociceptive transmission in the spinal cord depending on (i) its concentration, with high concentrations being antinociceptive and low concentrationPLOS ONE | DOI:10.1371/journal.pone.0142919 November 13, 2015Galanin Induces Hyperalgesia through Two Pain Descending PathwaysFoundation, Helsinki, Finland
Three days after the intrasynovial injection of K/C, all animals in the assessed in monoarthritic (ARTH) group developed a clear swelling of the treated right knee joint and all vocalized during a minor extension and flexion of the affected limb by the experimenter
Mechanical hyperalgesia in the knee joint was assessed by determining limb withdrawal threshold (LWT) during the application of pressure to the doi:10.1371/journal.pone.0142919.g001
Summary
The experiments were performed using adult male Hannover–Wistar rats (220–260 g; n = 12, Harlan, Horst, The Netherlands) in the Biomedicum Helsinki, Finland. All experiments were approved by the ethical committee for experimental animals studies of the State Provincial Office of Southern Finland (Hämeenlinna, Finland) and the experiments were performed according to the guidelines of European Communities Council Directive of 22nd September 2010 (2010/63/EU). The animals were housed in polycarbonate cages with a deep layer of saw dust, one animal in each cage, in a thermo-statically controlled room at 24.0 ± 0.5°C. The room was artificially illuminated from 8.30 a.m. to 8.30 p.m. The animals received commercial pelleted rat feed (CRM-P pellets, Special Diets Services, Witham, Essex, England) and water ad libitum
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