Downregulation of connexin36 in mouse spinal dorsal horn neurons leads to mechanical allodynia.
Connexin36 (Cx36), a component of neuronal gap junctions, is crucial for interneuronal communication and regulation. Gap junction dysfunction underlies neurological disorders, including chronic pain. Following a peripheral nerve injury, Cx36 expression in the ipsilateral spinal dorsal horn was markedly decreased over time, which paralleled the time course of hind paw tactile allodynia. Intrathecal (i.t.) injection of Cx36 siRNA (1 and 5 pg) significantly reduced the expression of Cx36 protein in the lumbar spinal cord, peaking 3 days after the injection, which corresponded with the onset of hind paw tactile allodynia. It is possible that some of the tactile allodynia resulting from Cx36 downregulation could be mediated through excitatory neuromodulators, such as glutamate and substance P. The Cx36 knockdown-evoked tactile allodynia was significantly attenuated by i.t. treatment with the N-methyl-D-aspartate glutamate receptor antagonist MK-801 but not the substance P receptor antagonist CP96345. Immunohistochemistry showed that Cx36 was colocalized with glycine transporter-2, a marker for inhibitory glycinergic spinal interneurons, but not with glutamate decarboxylase 67, a marker for inhibitory GABAergic spinal interneurons. The results indicate that spinal inhibition through glycinergic interneurons is reduced, leading to increased glutamatergic neurotransmission, as a result of Cx36 downregulation. The current data suggest that gap junction dysfunction underlies neuropathic pain and further suggest a novel target for the development of analgesics.
Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Yoki
Y
Nakamura
Norimitsu
N
Morioka
Fang Fang
FF
Zhang
Kazue
K
Hisaoka-Nakashima
Yoshihiro
Y
Nakata
D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D020671:Posterior Horn Cells / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D020426:Sciatic Neuropathy / Q000150:complications* / Q000473:pathology*; D000097004:Gap Junction delta-2 Protein
D001713:Biphenyl Compounds; D017630:Connexins; D016291:Dizocilpine Maleate; D005968:Glutamate Decarboxylase; D050487:Glycine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D000097004:Gap Junction delta-2 Protein; C493270:Slc6a5 protein, mouse; C402565:glutamate decarboxylase 1; C066892:CP 96345
connexin36; glutamate; glycine; neuronal gap junction; neuropathic pain