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The Role of GABA_A Receptor δ Subunit and its Agonist THIP in Thermal Hypersensitivity in a Mouse Model of Neuropathic Pain

Saya Hakata, Ayako Takahashi*, Akira Iura, Seiichi Osako, Hironobu Uematsu, Yoichi Matsuda and Yuji Fujino

Decreased gamma-aminobutyric acid (GABA)-mediated phasic inhibitory transmission in the spinal cord is thought to be responsible for the development of neuropathic pain. However, the role of GABAergic tonic current in substantia gelatinosa (SG) neurons remains to be fully elucidated. Using real-time polymerase chain reaction, we investigated the expression of the GABAA receptor δ subunit, which contributes to tonic current in the SG, in chronic constriction injury (CCI; a well-known model of neuropathic pain) and naive mice. The expression of the δ subunit mRNA was reduced by 40% in the ipsilateral SG of the dorsal horn of CCI mice compared to naive mice. We also performed behavioral experiments to assess the effect of the δ subunit-preferring agonist 4,5,6,7- tetrahydroisoxazolo(5,4-c)pyridine-3-ol (THIP) on thermal hypersensitivity with the Hargreaves test. Intrathecal administration of THIP significantly improved thermal thresholds of the ipsilateral hindpaw (4.55 ± 0.78 to 6.56 ± 1.09 s from baseline to after injection, respectively, P<0.005), while normal saline did not (4.41 ± 0.86 to 4.46 ± 1.1 s, P>0.1). GABAA receptor δ subunit-mediatedtonic current contributes to thermal hypersensitivity of CCI mice, and THIP may represent a therapeutic tool to improve thermal hypersensitivity.