Calcium signalling through L-type calcium channels: role in pathophysiology of spinal nociceptive transmission.

L-type voltage-gated calcium channels are ubiquitous channels in the CNS. L-type calcium channels (LTCs) are mostly post-synaptic channels regulating neuronal firing and gene expression. They play a role in important physio-pathological processes such as learning and memory, Parkinson's disease, autism and, as recognized more recently, in the pathophysiology of pain processes. Classically, the fundamental role of these channels in cardiovascular functions has limited the use of classical molecules to treat LTC-dependent disorders. However, when applied locally in the dorsal horn of the spinal cord, the three families of LTC pharmacological blockers - dihydropyridines (nifedipine), phenylalkylamines (verapamil) and benzothiazepines (diltiazem) - proved effective in altering short-term sensitization to pain, inflammation-induced hyperexcitability and neuropathy-induced allodynia. Two subtypes of LTCs, Cav 1.2 and Cav 1.3, are expressed in the dorsal horn of the spinal cord, where Cav 1.2 channels are localized mostly in the soma and proximal dendritic shafts, and Cav 1.3 channels are more distally located in the somato-dendritic compartment. Together with their different kinetics and pharmacological properties, this spatial distribution contributes to their separate roles in shaping short- and long-term sensitization to pain. Cav 1.3 channels sustain the expression of plateau potentials, an input/output amplification phenomenon that contributes to short-term sensitization to pain such as prolonged after-discharges, dynamic receptive fields and windup. The Cav 1.2 channels support calcium influx that is crucial for the excitation-transcription coupling underlying nerve injury-induced dorsal horn hyperexcitability. These subtype-specific cellular mechanisms may have different consequences in the development and/or the maintenance of pathological pain. Recent progress in developing more specific compounds for each subunit will offer new opportunities to modulate LTCs for the treatment of pathological pain with reduced side-effects. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Group I metabotropic glutamate receptor plasticity after peripheral inflammation alters nociceptive transmission in the dorsal of the spinal cord in adult rats.

Abstract: The dorsal horn of the spinal cord is a crucial site for pain transmission and modulation. Dorsal horn neurons of the spinal cord express group I metabotropic glutamate receptors (group I mGluRs) that exert a complex role in nociceptive transmission. In particular, group I mGluRs promote the activation of L-type calcium channels, voltage-gated channels involved in short- and long-term sensitization to pain. In this study, we analyzed the role of group I mGluRs in spinal nociceptive transmission and the possible cooperation between these receptors and L-type calcium channels in the pathophysiology of pain transmission in the dorsal horn of the spinal cord. We demonstrate that the activation of group I mGluRs induces allodynia and L-type calcium channel-dependent increase in nociceptive field potentials following sciatic nerve stimulation. Surprisingly, in a model of persistent inflammation induced by complete Freund's adjuvant, the activation of group I mGluRs induced an analgesia and a decrease in nociceptive field potentials. Among the group I mGluRs, mGluR1 promotes the activation of L-type calcium channels and increased nociceptive transmission while mGluR5 induces the opposite through the inhibitory network. These results suggest a functional switch exists in pathological conditions that can change the action of group I mGluR agonists into possible analgesic molecules, thereby suggesting new therapeutic perspectives to treat persistent pain in inflammatory settings.

Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain.

KEY POINTS: L-type calcium channels in the CNS exist as two subunit forming channels, Cav1.2 and Cav1.3, which are involved in short- and long-term plasticity. We demonstrate that Cav1.3 but not Cav1.2 is essential for wind-up. These results identify Cav1.3 as a key conductance responsible for short-term sensitization in physiological pain transmission. We confirm the role of Cav1.2 in a model of long-term plasticity associated with neuropathic pain. Up-regulation of Cav1.2 and down-regultation of Cav1.3 in neuropathic pain underlies the switch from physiology to pathology. Finally, the results of the present study reveal that therapeutic targeting molecular pathways involved in wind-up may be not relevant in the treatment of neuropathy. ABSTRACT: Short-term central sensitization to pain temporarily increases the responsiveness of nociceptive pathways after peripheral injury. In dorsal horn neurons (DHNs), short-term sensitization can be monitored through the study of wind-up. Wind-up, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels. In the dorsal horn of the spinal cord, two L-type calcium channels are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. In the present study, we used a mathematical model of DHNs in which we integrated the specific patterns of expression of each Cav subunits. This mathematical approach reveals that Cav1.3 is necessary for the onset of wind-up, whereas Cav1.2 is not and that synaptically triggered wind-up requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits and confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, although a clear mechanical allodynia dependent on Cav1.2 expression was observed after SNL, the amplitude of wind-up was decreased. These results were confirmed with our model when adapting Cav1.3 conductance to the changes observed after SNL. Finally, our mathematical approach predicts that, although wind-up amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and wind-up are not fully equivalent. Wind-up and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore confirming that short- and long-term sensitization are two different phenomena triggered by distinct mechanisms.