The Novel Gabapentinoid Mirogabalin Prevents Upregulation of α2δ-1 Subunit of Voltage-Gated Calcium Channels in Spinal Dorsal Horn in a Rat Model of Spinal Nerve Ligation.

Gabapentinoids are specific ligands for the α2δ-1 subunit of voltage-gated calcium channels. This class of drugs, including gabapentin and pregabalin, exert various pharmacological effects and are widely used for the treatment of epilepsy, anxiety, and chronic pain. The mechanism of action of gabapentinoids involves both direct modulation of calcium channel kinetics and inhibition of channel trafficking and expression, which contribute to the above pharmacological effects. In the present study, we investigated the effects of mirogabalin, a novel potent gabapentinoid, on expression levels of the α2δ-1 subunit in the spinal dorsal horn in a rat model of spinal nerve ligation (SNL) as an experimental animal model for peripheral neuropathic pain. The neuropathic pain state was induced by SNL in male Sprague - Dawley rats. After the development of mechanical hypersensitivity, the animals received 10 mg/kg mirogabalin or vehicle orally for 5 consecutive days and were subjected to immunohistochemical analysis of α2δ-1 subunit expression in the spinal cord. In the SNL model rats, expression of the α2δ-1 subunit significantly increased in the spinal dorsal horn at the ipsilateral side of nerve injury, while mirogabalin inhibited this increase. In conclusion, the α2δ-1 subunit was upregulated in the spinal dorsal horn of SNL model rats, and repeated administration of mirogabalin inhibited this upregulation. The inhibitory effect of mirogabalin on upregulation of the α2δ-1 subunit after nerve injury is considered to contribute to its analgesic effects in peripheral neuropathic pain.

Domon Y ，Kobayashi N ，Kubota K ，Kitano Y ，Ueki H ，Shimojo Y ，Ishikawa K ，Ofune Y ... -  《-》

Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia.

Li CY ，Song YH ，Higuera ES ，Luo ZD ... -  《-》

Upregulation of calcium channel alpha-2-delta-1 subunit in dorsal horn contributes to spinal cord injury-induced tactile allodynia.

Spinal cord injury (SCI) commonly results not only in motor paralysis but also in the emergence of neuropathic pain (NeuP), both of which can impair the quality of life for patients with SCI. In the clinical field, it is well known that pregabalin, which binds to the voltage-gated calcium channel alpha-2-delta-1 (α2δ-1) subunit has therapeutic effects on NeuP after SCI. A previous study has demonstrated that SCI increased α2δ-1 in the L4-L6 dorsal spinal cord of SCI rats by Western blot analysis and that the increase of α2δ-1 was correlated with tactile allodynia of the hind paw. However, the detailed feature of an increase in α2δ-1 protein in the spinal dorsal horn and the mechanism of pregabalin effect on SCI-induced NeuP have not been fully examined. This study aimed to examine the detailed distribution of α2δ-1 expression in the lumbar spinal cord after thoracic SCI in rats and the correlation of the therapeutic effect of pregabalin in SCI rats. Male Sprague-Dawley rats underwent thoracic (T10) spinal cord contusion injury using the IH impactor device. Spinal cord injury rats received pregabalin (30 mg/kg) once a day for 2 weeks over a 4-week period after SCI. The mechanical threshold in the rat hind paw was measured over 4 weeks. Alpha-2-delta-1 expression in the lumbar spinal cord and in the dorsal root ganglion (DRG) was analyzed using immunohistochemistry and in situ hybridization histochemistry. A significant reduction of the withdrawal threshold of mechanical stimuli to the hind paw was observed for 2 weeks and continued at least 4 weeks after SCI. In the control rats, expression of α2δ-1 immunoreactivity was detected mainly in laminae I and II in the lumbar dorsal horn. Thoracic SCI significantly increased α2δ-1 immunoreactivity in laminae I and II in the lumbar dorsal horn 4 weeks after SCI; however, thoracic SCI did not affect the expression of α2δ-1 mRNA in the L4 and L5 DRGs. Meanwhile, the signal intensity of α2δ-1 mRNAs in the lumbar spinal cord increased from Day 7 and continued for at least 28 days after SCI. Cellular analysis showed that SCI increased the number of α2δ-1-expressing cells in laminae I and II. The tactile allodynia of the hind paw in the SCI rats was reversed after pregabalin treatment and was maintained for 21 days. This administration of pregabalin decreased the α2δ-1 immunoreactivity significantly in the lumbar dorsal horn of thoracic SCI rats at 28 days after SCI. The present study results suggest that an increase of α2δ-1 in the L4 and L5 dorsal horns after thoracic SCI is derived from the increase in the expression in lumbar spinal neurons. This increase may be involved in the development of NeuP in the hind paws and the therapeutic effect of pregabalin on central NeuP after SCI.

Kusuyama K ，Tachibana T ，Yamanaka H ，Okubo M ，Yoshiya S ，Noguchi K ... -  《-》

Mirogabalin activates the descending noradrenergic system by binding to the α(2)δ-1 subunit of voltage-gated Ca(2+) channels to generate analgesic effects.

Oyama M ，Watanabe S ，Iwai T ，Tanabe M ... -  《-》

Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the α(2)δ Subunit of Voltage-Gated Calcium Channels.

Mirogabalin ([(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the α2δ subunit of voltage-gated calcium channels, is being developed to treat pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. In the present study, we investigated the in vitro binding characteristics and in vivo analgesic effects of mirogabalin compared with those of pregabalin, a standard α2δ ligand. Mirogabalin showed potent and selective binding affinities for the α2δ subunits, while having no effects on 186 off-target proteins. Similar to pregabalin, mirogabalin did not show clear subtype selectivity (α2δ-1 vs. α2δ-2) or species differences (human vs. rat). However, in contrast to pregabalin, mirogabalin showed greater binding affinities for human α2δ-1, human α2δ-2, rat α2δ-1, and rat α2δ-2 subunits; further, it had a slower dissociation rate for the α2δ-1 subunit than the α2δ-2 subunit. Additionally, in experimental neuropathic pain models, partial sciatic nerve ligation rats and streptozotocin-induced diabetic rats, mirogabalin showed more potent and longer lasting analgesic effects. In safety pharmacological evaluations, mirogabalin and pregabalin inhibited rota-rod performance and locomotor activity in rats; however, the safety indices of mirogabalin were superior to those of pregabalin. In conclusion, mirogabalin shows potent and selective binding affinities for the human and rat α2δ subunits, and slower dissociation rates for the α2δ-1 subunit than the α2δ-2 subunit. It shows potent and long-lasting analgesic effects in rat models of neuropathic pain, and wider safety margins for side effects of the central nervous system. These properties of mirogabalin can be associated with its unique binding characteristics.

Domon Y ，Arakawa N ，Inoue T ，Matsuda F ，Takahashi M ，Yamamura N ，Kai K ，Kitano Y ... -  《-》