Transmission of nociceptive signalling and mechanisms underlying its modulation

Abstract

Specific features of calcium signalling in neurons of the nociceptive system, in particular in primary afferent (dorsal root ganglion) and secondary dorsal horn spinal units, are described. The roles of different types of calcium channels and intracellular Ca stores (those of the mitochondria and endoplasmic reticulum) and interactions between these cellular structures in the norm and under pathological conditions (in particular in diabetic neuropathy) are discussed.It is well known that calcium signalling plays a great and, in many cases, even crucial role in such processes as exocytosis, translation of intracellular signals in nerve cells, synaptic transmission, synaptic plasticity, cell division, and even in such events as apoptosis and cell necrosis. Increases in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) usually enhance most of these processes, including the transmitter release, while excessive rises in the [Ca 2+ ] i can suppress them and can even lead to dangerous negative consequences with respect to the cell. Calcium signalling is provided by a variety of the [Ca 2+ ] i -regulated structures that interact in a rather complex manner; compensatory Ca 2+ entry is one of the aspects of such interaction.Calcium signalling in the cells of nociceptive neuronal networks plays a great role in the somatosensory system in general. Translation of the pain sensitivity begins at the level of primary afferent somatosensory neurons, namely of cells of the dorsal root ganglia (DRG). Among DRG cells of different sizes, small-and medium-sized units connected with Aγ and C afferent fibers are involved in the process of nociception. Sensory information encoded by the corresponding receptor structures (including free peripheral terminals of thin afferent fibers) is transferred to the brain mostly via the spino-thalamic tract. Large DRG neurons (somata of proprioceptive and relatively low-threshold cutaneous afferent units) do not participate in this process [1]. Transduction of calcium signals in the above types of DRG neurons is characterized by certain specific features [2].In DRG neurons, calcium signals are primarily formed to a great extent due to high-rate Ca 2+ entry through high and low voltage-operated calcium channels that dominate in this kind of cells. Then, calcium signals undergo certain modulations due to the functioning of the mitochondria, endoplasmic reticulum (ER), a few Ca 2+ -ATPases, and Ca 2+ exchangers [3,4] It is of interest that the mitochondria are, in most cases, located in small DRG neurons in close proximity to the cell membrane; they provide rapid uptake of Ca 2+ from the cytosol and rather slowly return of these ions back; this is why a long-lasting residual elevation of [Ca 2+ ] i in the cytoplasm is observed. Such a situation noticeably influences production of energy (in the form of ATP) in nociceptive neurons. The mitochondria maintain a high level of Ca 2+ in primary nociceptive (small) DRG neurons that probably are the first structures in the CNS specifically responding to the Ca...

Peculiarities of Ion Channels and Modulation of Their Functions in Neurons Belonging to the Nociceptive System

“…Nociceptive afferent fibers are processes of afferent neurons with a relatively small diameter of the somata (small-and mid-sized neurons of the sensory ganglia); in other words, the size of the soma of such neurons and their belonging to the system of nociception demonstrate rather close correlation. This peculiarity has been mentioned in numerous publications; its description in a few papers [1][2][3] was close to the topic of our review.…”

“…Calcium currents through the membrane of nociceptive primary afferent neurons are due to the existence of voltage-dependent calcium channels of types L, T, N, R, and P/Q [1,2]. The activation of high-threshold N-type calcium channels is closely related to generation of nociceptive signals; it was found that these N-type channels are sensitive to changes in the temperature.…”

“…The state of the mitochondria can be directly influenced by agonists and antagonists of VR1; the effects of other intracellular molecules cannot be ruled out [34]. It should be taken into account that calcium signaling can, in different manners, influence the mitochondria in primary afferent neurons (and, probably, in the first central neurons) depending on the peculiarities of localization of these organelles (in close proximity to external membrane or at a certain distance from it) [2].…”