Presynaptic Inhibition of Primary Nociceptive Signals to Dorsal Horn Lamina I Neurons by Dopamine

Abstract

The dorsal horn of the spinal cord represents the first relay station in the pain pathway where primary nociceptive inputs are modulated by local circuits and by descending signals before being relayed to supraspinal nuclei. To determine whether dopamine can modulate primary nociceptive Aδ- and C-fiber signals, the effects of dopamine were tested on the excitatory postsynaptic currents (EPSCs) recorded from large lamina I neurons and from retrograde-labeled spinoparabrachial lamina I neurons upon stimulation of the L4/L5 dorsal root in horizontal spinal cord slices Dopamine inhibited the EPSCs in a dose-dependent manner, with substantial inhibition (33%) at 1 μm and maximum inhibition (∼70%) at 10-20 μm Dopamine reduced the frequency of miniature EPSCs recorded from large lamina I neurons, increased the paired pulse depression ratio of paired EPSCs, and induced similar inhibition of EPSCs after dialysis of large lamina I neurons with GDP-β-S, consistent with actions at presynaptic sites. Pharmacological experiments suggested that the inhibitory effects of dopamine were largely mediated by D4 receptors (53%). Similar inhibition (66%) by dopamine was observed on EPSCs recorded from ipsilateral large lamina I neurons 6 d after injection of complete Freund's adjuvant in the hindpaw, suggesting that dopamine downregulates primary nociceptive inputs to lamina I neurons during chronic inflammatory pain. We propose that presynaptic inhibition of primary nociceptive inputs to lamina I projection neurons is a mechanism whereby dopamine can inhibit incoming noxious stimuli to the dorsal horn of the spinal cord. Lamina I projection neurons represent the main output for the pain signals from the dorsal horn of the spinal cord to brainstem and thalamic nuclei. We found that dopamine inhibits the nociceptive Aδ- and C-fiber synaptic inputs to lamina I projection neurons via presynaptic actions. Similar inhibitory effects of dopamine on the EPSCs were observed in rats subjected to complete Freund's adjuvant to induce peripheral inflammation, suggesting that dopamine inhibits the synaptic inputs to lamina I neurons in the setting of injury. A better understanding of how primary nociceptive inputs to the dorsal horn of the spinal cord are modulated by descending monoaminergic signals may help in the development of new pharmacological strategies to selectively downregulate the output from lamina I projection neurons.

<p>Deep sequencing analysis to identify novel and rare variants in pain-related genes in patients with acute postoperative pain and high morphine use</p>

“…Five of the genes in Table 5 are involved in the cocaine addiction pathway. Based on experimental studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effect 40–42. Cocaine increases the level of dopamine and cocaine addiction is related to pain 43.…”

Projection Neuron Axon Collaterals in the Dorsal Horn: Placing a New Player in Spinal Cord Pain Processing

“…The final element identified in the original gate control theory is “central control,” where signals arising from the brain itself descend and modify spinal dorsal horn activity. Indeed, several brain structures are now well-established sources of descending input to the spinal dorsal horn ( Suzuki et al, 2004 ; François et al, 2017 ; Lu et al, 2018 ). They have the capacity to facilitate or inhibit dorsal horn circuits and alter the gain of pain signaling in this region.…”

Hypothalamic A11 Nuclei Regulate the Circadian Rhythm of the Mechanonociception and the Spinal Clock Gene Transcription through Dopamine Receptor Activation

“…These data suggest that activation of spinal D1 and D5 receptors participates in the antiallodynic effect. Since these are stimulatory receptors, activation of D1-like receptors should lead to a pronociceptive effect [12,25]. However, there is evidence that spinal activation of D1-like receptors by low concentrations of DA depresses ventral root potential, which is a C fiber-evoked polysynaptic response and believed to reflect nociception [25].…”

“…Nociception is a complex process integrated by the primary afferent fibers, dorsal horn of the spinal cord, ascending and descending supraspinal pathways, and higher brain centers [2,[11][12][13]. In recent years, there has been an increased interest in analyzing the descending modulatory pathways of nociception at the spinal cord, particularly noradrenergic, serotonergic, and dopaminergic fibers [2,[14][15][16][17][18].…”