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  • There is a dual inducer of both galanin and super

    2022-05-26

    There is a dual inducer of both galanin and super-threshold pain. First, injury-induced pain may stimulate galanin secretion. After peripheral nerve injury, the galanin expression level was upregulated in dorsal root ganglion (DRG), dorsal horn and hypothalamic arcuate of rats [25], [28], [33]. The cyclophosphamide-induced cystitis significantly enhanced galanin mRNA expression levels in arcuate nucleus and PVN as well as galanin levels in the hypothalamic and limbic nuclei of algesic mice [55]. After unilateral loose ligation of the sciatic nerve, the GalR1-positive neurons were significantly increased in the ipsilateral tuberomammillary nucleus compared with the contralateral tuberomammillary nucleus or in the nucleus of intact rats [68]. Interestingly, during status epilepticus galanin was depleted from axonal projections of locus coeruleus and septum/diagonal band neuronspus. Then GalR2 mRNA expression and GalR2 receptor protein levels were downregulated by 30%, whilst the quantity of GalR1 receptors was not altered in a subset of hippocampus [50]. Second, a lot of evidences indicated that galanin reduced nociception and pain transmission in different areas of DiscoveryProbe™ Inhibitor Library and produced antinociception in spinal cord and arcuate nucleus of hypothalamus [11], [13], [22], [75]. Galanin may decrease the acute pain sensitivity in animals [40], [62]. The galanin over-expressing transgenic mice have higher nociceptor thresholds, lower spontaneous neuronal firing and C-fiber barrage into the spinal cord than wild type controls [31]. These mice markedly reduced neuropathic pain-like behavior and response intensity to mechanical and thermal allodynia, which may be blocked by intrathecal administration of galanin antagonist M35 [11], [27], [32], [76], [77]. While the Gal-KO mice had higher sensitivity to acute mechanical and thermal pain than controls, as well as increased the response intensity to neuropathic pain [35]. In addition, there is an antinociceptive effect of exogenous galanin on the chronic pain, such as neuropathic and inflammatory pain in animals [3], [57]. Galanin inhibited nociception of intact or neuropathic pain animals [27]. These results indicate that galanin may reduce both acute and chronic pain sensitivity in animals. Third, numerous studies demonstrated that galanin may regulate pain threshold via central GalR1 [21], [78]. The anatomical and behavioral studies indicated that GalR1-expressing neurons in the dorsal horn were involved in modulation of thermal nociception. And loss of these neurons produced thermal hypo-algesia [44]. Intracerebroventricular administration of galanin, or GalR1 agonist M617, or both of galanin and M617 markedly increased the hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in rats [21]. There are no significant differences between M617- or galanin-induced antinociceptive effects, suggesting that galanin plays antinociceptive roles mainly via central GalR1 in the brain of rats. GalR1-KO mice developed modest hyperalgesia after injury and inflammation, as well as increased duration of neuropathic pain-like behavior [10], [53]. These results support that the central galanin is via GalR1 to regulate nociceptive processing of subjects. Finally, galanin may also regulate pain threshold via peripheral GalR2 in the DRG. The peripheral GalR2, as a potential analgesic target, was activated by high concentration galanin to enhance the threshold of mechanical nociceptors and to reduce ongoing nociceptive responses in the rats with injured nerves [31]. As the expression of GalR3 mRNA in the DRG is undetectable in the in situ hybridization test, the GalR2/3 agonist, galanin (2–11), is taken as an activator of GalR2 in the DRG. The respective or cooperative subcutaneous injection with galanin and galanin (2–11) into the nociceptive receptive field altered the neuropathic pain threshold in rats and mice with injured partial saphenous nerve, with low concentrations facilitating and high concentrations inhibiting nociceptor activity [31]. While both galanin and GalR2 knockout animals lost a specific subset of sensory neurons and lessened neuropathic and inflammatory pain behavior [25], [64]. And a lack of GalR2 activation in Gal-KO mice or GalR2-mutant animals have decreased neurite outgrowth from sensory neurons in DRG and impaired pain-like behavior [25].