Regulatory Action of Calcium and Calcium Channels in Pain Pathways

Abstract

Calcium ions (Ca²⁺) and Ca²⁺ channels are pivotal in the regulation of pain pathways and serve as key regulators of neuronal excitability and neurotransmitter release. We review the different types of Ca²⁺ channels involved in pain processing, including voltage-gated Ca²⁺ channels (VGCCs), such as L-, N-, P/Q-, and T-type channels. Each subtype is intricately involved in different aspects of pain perception, from acute pain signaling to the development and maintenance of chronic pain states. In addition, the roles of transient receptor potential (TRP) channels, particularly TRPV1 and TRPA1, are discussed in the context of their contribution to chronic pain. Advances in Ca²⁺ imaging techniques, particularly through genetically encoded Ca²⁺ indicators (GECIs), such as GCaMPs, have provided unprecedented insight into the dynamic role of Ca²⁺ channels in pain pathways. These efforts have deepened our understanding of Ca²⁺ channels and suggest novel therapeutic targets for more effective pain management strategies within Ca²⁺ channels.

Keywords: Ca2+, Ca2+ channel; GCaMP; GECI; TRP channel; VGCC; pain; regulatory mechanism.

Figure 1

Depiction of the journey of pain signals from peripheral tissues to the brain, where they are ultimately perceived as pain. Pain signals are initiated in specialized sensory nerve endings called nociceptors, located in the skin, muscles, and organs (e.g., visceral tissues). In these nociceptors, Ca²⁺-permeable channels, TRPV1 and TRPA1, play a key role in detecting noxious stimuli, such as mechanical injury, temperature extremes (hot or cold), and chemical irritants. When these channels are activated, pain signals are initiated. Transmission of these pain signals to the central nervous system is facilitated by voltage-gated Ca²⁺ channels (VGCCs) in the presynaptic terminals of the spinal cord, which trigger the release of neurotransmitters and allow the continuation of the pain signal through the ascending pathways. VGCCs play a key role in pain modulation by affecting the intensity and duration of pain signals within the spinal cord and higher brain regions, ultimately influencing the perception and experience of pain.

Figure 2

In vivo fluorescence imaging of dorsal root ganglion (DRG) during inflammation using Pirt-GCaMP3 mice. A. (top) Control mice received mock injection in right hindpaw; (bottom) Experimental mice received injection of complete Freund's adjuvant (CFA) into the right hindpaw to induce inflammation. For both mice, two days later, the DRG was surgically exposed at the right lumbar L5, which innervates the right hindpaw and examined by Ca²⁺ imaging. B. Representative confocal fluorescence images of the L5 DRG showing GCaMP3 expression in primary sensory neurons (green). At baseline, naïve mouse (panel a) showed few steady-state high Ca²⁺ level cells and Ca²⁺oscillated cells (spontaneous activity), whereas CFA-treated mouse (panel c) exhibited some steady-state high Ca²⁺ level cells and Ca²⁺oscillated cells (indicated by greener and brighter neurons). Among mice that received a 100-g mechanical press delivered to the right hindpaw (panel b, d), there was an increase in the number of activated DRG neurons (indicated by greener and brighter neurons), and the increase was much greater in the CFA-treated mice than in the control mice (compare panels b & d). Scale bar: 100 μm.