Upregulation of Dorsal Root Ganglion α₂δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats

Abstract

Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the ␣ 2 ␦-1 (hereafter referred to as ␣ 2 ␦) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered ␣ 2 ␦ subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a Ͼ17-fold, time-dependent increase in ␣ 2 ␦ subunit expression in DRGs ipsilateral to the nerve injury. Marked ␣ 2 ␦ subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased ␣ 2 ␦ subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG ␣ 2 ␦ regulation was at the mRNA level. In contrast, calcium channel ␣ 1B and ␤ 3 subunit expression was not co-upregulated with the ␣ 2 ␦ subunit after nerve injury. These data suggest that DRG ␣ 2 ␦ regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development. Key words: ␣ 2 ␦ calcium channel subunit; peripheral nerve injury; rhizotomy; allodynia; dorsal root ganglia; spinal cord; sensory neuronsPeripheral nerve injury may lead to neuropathic syndromes characterized by both spontaneous and evoked painful sensations. Allodynia, or an exaggerated response to otherwise innocuous tactile stimuli, is considered both a hallmark and the most troublesome of these syndromes (Price et al., 1989;Wahren and Torebjork, 1992;Koltzenburg et al., 1994). The molecular mechanisms of neuropathic pain states are not clear. It has been hypothesized that disordered sensory processing arises from long-term changes in the function of sensory afferents and the organization of sensory input into the dorsal horn (Coderre et al., 1993;Woolf and Doubell, 1994).Pharmacological evidence suggests that spinal N-type voltagegated calcium channels (N-VGCCs) play a role in neuropathic pain transduction. Intrathecal delivery of N-type ( -conopeptides), but not L-or P-type, VGCC antagonists suppresses allodynia in neuropathic rat models (Chaplan et al., 1994b;Calcutt and Chaplan, 1997). Autoradiographic studies showed the highest density of conopeptide-binding sites in the spinal dorsal horn (lamina I and II) where primary afferents terminate (Kerr et al., 1988;Takemura et al., 1989). N-VGCCs are also found in dorsal root ganglion (DRG) neurons where they are differentially modulated after sciatic nerve damage (Abdulla and Smith, 1997).High-threshold neuronal VGCCs contain thr...

Neuropathic Pain Management in Chronic Laminitis

“…115,116 The expression of the α 2 δ-1 subunit has been shown to increase in chronic pain states, as well as in both afferent sensory neurons and in the spinal cord dorsal horn in experimental neuropathic pain models. 117,118 This correlates well with the observation that gabapentin exerts analgesic properties primarily in sensitized or hyperalgesic states. 119,120,121 More recently gabapentin and pregabalin have been used clinically in humans to treat a variety of neuropathic pain states and early post-surgical pain, often but not always with success.…”

Transport of receptors, receptor signaling complexes and ion channels via neuropeptide-secretory vesicles

“…Such a mechanism may also have functional impact in pain therapies. Indeed, the VGCC α2δ1 subunit serves as a target protein for gabapentin and pregabalin, drugs used for the clinical treatment of certain types of chronic pain [54][55][56]. The LDCV localization of VGCC α2δ1 would enable a stimulus-induced cell-surface expression of this Ca 2+ channel subunit.…”

Gabapentin Supplemented With Ropivacain Block of Trigger Points Improves Pain Control and Quality of Life in Trigeminal Neuralgia Patients When Compared With Gabapentin Alone

“…49,50 Calcium channels are essential for modulation of cell-membrane excitability and thus are implicated in neuropathic pain, 51 with the expression of the a2d subunit being increased in some neuropathic models. 52 These channels are also essential for the release of central neurotransmitters from axonal terminal boutons to the synaptic gap 51 and pregabalin (a close structural relative of GBP) binding to the a2d subunit reduces their presynaptic liberation. 53 The importance of this effect in GBP action is not known as ACs that act synaptically (eg, barbiturates) are largely ineffective as analgesics.…”