Inhibition of Tetrodotoxin-Resistant Sodium Current in Dorsal Root Ganglia Neurons Mediated by D1/D5 Dopamine Receptors

Abstract

BackgroundDopaminergic fibers originating from area A11 of the hypothalamus project to different levels of the spinal cord and represent the major source of dopamine. In addition, tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines, is expressed in 8-10% of dorsal root ganglia (DRG) neurons, suggesting that dopamine may be released in the dorsal root ganglia. Dopamine has been shown to modulate calcium current in DRG neurons, but the effects of dopamine on sodium current and on the firing properties of small DRG neurons are poorly understood.ResultsThe effects of dopamine and dopamine receptor agonists were tested on the tetrodotoxin-resistant (TTX-R) sodium current recorded from acutely dissociated small (diameter ≤ 25 μm) DRG neurons. Dopamine (20 μM) and SKF 81297 (10 μM) caused inhibition of TTX-R sodium current in small DRG neurons by 23% and 37%, respectively. In contrast, quinpirole (20 μM) had no effects on the TTX-R sodium current. Inhibition by SKF 81297 of the TTX-R sodium current was not affected when the protein kinase A (PKA) activity was blocked with the PKA inhibitory peptide (6–22), but was greatly reduced when the protein kinase C (PKC) activity was blocked with the PKC inhibitory peptide (19–36), suggesting that activation of D1/D5 dopamine receptors is linked to PKC activity. Expression of D1and D5 dopamine receptors in small DRG neurons, but not D2 dopamine receptors, was confirmed by Western blotting and immunofluorescence analysis. In current clamp experiments, the number of action potentials elicited in small DRG neurons by current injection was reduced by ~ 30% by SKF 81297.ConclusionsWe conclude that activation of D1/D5 dopamine receptors inhibits TTX-R sodium current in unmyelinated nociceptive neurons and dampens their intrinsic excitability by reducing the number of action potentials in response to stimulus. Increasing or decreasing levels of dopamine in the dorsal root ganglia may serve to adjust the sensitivity of nociceptors to noxious stimuli.

Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons

“…This is consistent with the expression of D1 and D5 dopamine receptors both in peptidergic and non‐peptidergic DRG neurons (Galbavy et al . ).…”

“…; Galbavy et al . ). A question, however, remains about why it has been difficult to detect other enzymes necessary for the synthesis of catecholamines, i.e.…”

“…Recently we have provided evidence that stimulation of D1/D5 dopamine receptors results in reduction of tetrodotoxin‐resistant (TTX‐R) sodium current in nociceptors (Galbavy et al . ). Here, using an in vitro preparation of acutely dissociated DRG neurons, we show that dopamine downregulates TRPV1 channels expressed in small diameter (<27 μm) DRG neurons.…”

“…; Galbavy et al . ); (ii) recordings from neurons in lamina II–III in the dorsal horn spinal cord have suggested a postsynaptic effect of dopamine mediated by D2 dopamine receptors (Tamae et al . ; Taniguchi et al .…”

Dorsal root ganglion neurons and tyrosine hydroxylase—an intriguing association with implications for sensation and pain

“…Dopamine receptors 1–5 (D1–5Rs) have been reported in rat DRG neurons using RT-PCR [100], western blot and immunohistochemistry [23]. These receptors are functional, as established by the inhibitory effects of D1- and D2Rs [58,68], or D1- and D5Rs [23], on the electrical activity of predominantly small DRG neurons [23,58,68]. Such effects could modulate both the excitability of DRG nociceptors as well as neurotransmitter release from their central terminals.…”