Activation of the galanin receptor 2 in the periphery reverses nerve injury-induced allodynia

Exogenous galanin altered the responses of mechano-nociceptive C-fibre afferents in a dose-dependent manner in both naive and nerve injured animals, with low concentrations facilitating and high concentrations markedly inhibiting mechano-nociceptor activity. Further, use of the galanin fragment Gal2-11 confirmed that the effects of galanin were mediated by activation of galanin receptor-2 (GalR2). The inhibitory effects of peripheral GalR2 activation were further supported by our demonstration that after PSNI, mechano-sensitive nociceptors in galanin over-expressing transgenic mice had significantly higher thresholds than in wild type animals, associated with a marked reduction in spontaneous neuronal firing and C-fibre barrage into the spinal cord.These findings are consistent with the hypothesis that the high level of endogenous galanin in injured primary afferents activates peripheral GalR2, which leads to an increase in C-fibre mechanical activation thresholds and a marked reduction in evoked and ongoing nociceptive responses.The neuropeptide galanin is expressed at low levels in ~5% of small diameter neurons in the intact adult rodent dorsal root ganglion (DRG) [1-3]. Higher levels of the peptide are also detected in the primary afferent terminals of the spinal cord (lamina II), the dorsal horn inter-neurons [4], and in a number of brain regions known to modulate nociception, including the arcuate nucleus and periaqueductal grey (PAG) [5,6]. After nerve injury and models of neuropathic pain, galanin expression is markedly increased in 30-40% of sensory neurons [7,8] and in the primary afferent terminals in the superficial layers of the dorsal horn [9].Behavioural studies have demonstrated that intrathecal (i.t.) administration of galanin modulates nociception in a dose-dependent manner, with facilitation of nociceptive reflexes at low concentrations of galanin [10,11] and a striking inhibition at higher concentrations [12,13]. The anti-nociceptive effect of hig