Elevated galanin receptor type 2 primarily contributes to mechanical hypersensitivity after median nerve injury

Abstract

In this study, we investigated temporal changes in galanin receptor type 2 (GalR2) expression in NF200-, galanin-, neuropeptide Y (NPY)-, and neuronal nitric oxide synthase (nNOS)-like immunoreactive (LI) dorsal root ganglion (DRG) neurons after median nerve chronic constriction injury (CCI), and the effects of GalR2 on c-Fos expression in the cuneate nucleus (CN). Double immunofluorescence labeling methods were used to appraise changes in GalR2 expression in NF200-LI, galanin-LI, NPY-LI, and nNOS-LI DRG neurons after CCI. The von Frey assay was used to assess the efficiency of intraplantar administration of saline, M871 (a GalR2 antagonist), or AR-M1896 (a GalR2 agonist) on neuropathic signs of rats with CCI. The effects of alterations in c-Fos expression were assessed in all treatments. The percentage of GalR2-LI neurons in lesioned DRGs increased and peaked at 1 week after CCI. We further detected that percentages of GalR2-LI neurons labeled for NF200, galanin, NPY, and nNOS significantly increased following CCI. Furthermore, M871 remarkably attenuated tactile allodynia, but the sensation was slightly aggravated by AR-M1896 after CCI. Consequentially, after electrical stimulation of the CCI-treated median nerve, the number of c-Fos-LI neurons in the cuneate nucleus (CN) was significantly reduced in the M871 group, whereas it increased in the AR-M1896 group. These results suggest that activation of GalR2, probably through NPY or nitric oxide, induces c-Fos expression in the CN and transmits mechanical allodynia sensations to the thalamus.

Molecular Changes in the Dorsal Root Ganglion during the Late Phase of Peripheral Nerve Injury–induced Pain in Rodents: A Systematic Review

“…Galanin, another neuropeptide, was found to be increased on the protein level by four studies during the chronic phase in different pain models, namely sciatic nerve transection, spared nerve injury, L5 spinal nerve ligation, and chronic constriction injury, of which all were statistically significant except chronic constriction injury. 95,97–99 A significant increase of its receptor, galanin receptor type 2, was also found at 4 weeks after chronic constriction injury and spared nerve injury, mainly in the medium- to large-sized neurons. 97,99 The latest timepoint at which galanin was investigated was 55 weeks after injury, in a study that used two pain models (sciatic nerve transection and L5 spinal nerve ligation).…”

“…95,97–99 A significant increase of its receptor, galanin receptor type 2, was also found at 4 weeks after chronic constriction injury and spared nerve injury, mainly in the medium- to large-sized neurons. 97,99 The latest timepoint at which galanin was investigated was 55 weeks after injury, in a study that used two pain models (sciatic nerve transection and L5 spinal nerve ligation). 98 Interestingly, besides galanin + neurons, they also reported the presence of pericellular axonal rings containing galanin in the dorsal root ganglions after injury, which were not identified in naïve or contralateral dorsal root ganglions.…”

A New Gal in Town: A Systematic Review of the Role of Galanin and Its Receptors in Experimental Pain

“…After peripheral axotomy, galanin is dramatically upregulated and expressed in small-sized DRG neurons, with a shift towards its expression also in medium/large-sized neurons [ 10 , 51 , 53 , 54 , 55 , 56 , 57 , 58 , 96 , 111 , 145 ], both of which are accompanied by a retrograde increase in galanin in the spinal cord. Similar results were obtained after partial sciatic nerve ligation [ 59 , 145 , 146 ], cisplatin-induced neuronopathy [ 64 ], spinal nerve ligation [ 72 ], constriction/photochemically-induced sciatic nerve injury [ 62 , 63 , 65 , 66 , 67 , 71 , 76 ], in inferior alveolar neuromas [ 68 , 69 ], tibial nerve injury [ 51 , 77 , 147 ], diabetes-induced neuropathy [ 76 ], medial nerve injury [ 78 ], trigeminal nerve injury [ 70 ], Freud’s adjuvant-induced inflammation [ 79 , 145 ], collagen-induced arthritis [ 80 ], bone cancer [ 73 ], post-herpetic neuralgia [ 74 ] and HIV-associated neuropathic pain [ 148 ].…”

“…This phenomenon was also observed after axotomy, although with no apparent impact on the mechanical and thermal nociceptive responses [ 125 ]. Further evidence of a pronociceptive role of GalR2 was demonstrated when intraplantar administration of GalR2 agonist M1896 increased mechanical and thermal nociceptive responses after chronic constriction injury of the median nerve, with GalR2 antagonist M871 having an opposite effect [ 78 ]. However, different results were obtained after administration of a GalR2-preferring galanin analogue, which displayed an analgesic effect after carrageenan-induced induction and partial sciatic nerve ligation [ 127 ].…”

“…After inflammation or nerve injury, galanin receptors GalR1 and GalR2 show great expression plasticity at the spinal, the DRG, and the supraspinal levels. After peripheral nerve injury and inflammation, GalR1 was downregulated [ 16 , 76 , 120 ] while GalR2 was upregulated [ 16 , 76 , 78 , 118 , 124 , 126 ] in both the DRG and SDH. These results are consistent with a more pronociceptive action of GalR2 in the spinal cord, causing hypersensitivity to noxious stimulation and the consequent mechanical and thermal hyperalgesia observed in these animals.…”