Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.
In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury.
Department of Oral Diagnosis Science, Nihon University School of Dentistry, Tokyo, Japan; Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan. Electronic address: okada.akiko1@nihon-u.ac.jp.
Akiko
A
Okada-Ogawa
Department of Oral Diagnosis Science, Nihon University School of Dentistry, Tokyo, Japan.
Yuka
Y
Nakaya
Department of Oral Diagnosis Science, Nihon University School of Dentistry, Tokyo, Japan; Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan.
Yoshiki
Y
Imamura
Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan.
Masayuki
M
Kobayashi
Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan; Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan.
Masamichi
M
Shinoda
Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan.
Kozue
K
Kita
Department of Oral Physiology, Faculty of Dentistry, and Department of Physiology, faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Barry J
BJ
Sessle
Department of Physiology, Nihon University School of Dentistry, Tokyo, Japan; Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry, Tokyo, Japan; Division of Applied System Neuroscience Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan.
Koichi
K
Iwata
D000085:Acetates / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology*; D007192:Indenes / Q000494:pharmacology; D008340:Mandibular Nerve / Q000473:pathology / Q000601:surgery; D008526:Medulla Oblongata / Q000473:pathology*; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology*; D010812:Physical Stimulation; D051381:Rats; D055647:Rats, Transgenic; D013995:Time; D061221:Trigeminal Nerve Injuries / Q000150:complications* / Q000209:etiology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000085:Acetates; D058785:GABA-A Receptor Agonists; D005904:Glial Fibrillary Acidic Protein; D007192:Indenes; C118623:Slc32a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C095651:((2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy)acetic acid; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D048049:Extracellular Signal-Regulated MAP Kinases
Ectopic neuropathic pain; GABA; KCC2; Trigeminal nerve injury; Trigeminal spinal subnucleus caudalis