Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice

Abstract

Mas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist-induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects.

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

“…However, because these channels are broadly expressed throughout the peripheral nervous system and CNS, channel blockers pose side effects, such as nausea, anxiety, and sweating (57-59). BAM8-22 mainly inhibits N-type channels in DRG neurons from MrgprX1 mice, similar to what we found with MRGPRC activation (48). Whereas the activation of MRGPRC leads to inhibition of HVA I Ca through a phospholipase C-dependent mechanism, our findings suggest that MRGPRX1 inhibition of HVA I Ca is mainly mediated by G i/o -sensitive Gβγ binding and may also involve a Gβγ-independent pathway.…”

“…The paired-pulse ratio (PPR) is defined as the peak amplitude of the second eEPSC (P2) divided by the first eEPSC (P1) evoked by two pulses. The reduction of first eEPSCs by BAM8-22 with ML382 was associated with an increased PPR in MrgprX1 mice, suggesting presynaptic inhibition of excitatory neurotransmitter release (48,49). This phenomenon was not observed in Mrgpr −/− mice, and ML382 alone did not affect PPR.…”

“…5A). High-intensity paired-pulse stimulation (500 μA, 0.1 ms, 400 ms apart, three tests per minute) was applied at the dorsal root to activate high-threshold afferent fibers (C-fibers) (48). Bath application of 0.5 μM BAM8-22 induced a strong inhibition of first eEPSCs in 10 of 18 SG neurons (55.6%).…”

Reversal of neurochemical alterations in the spinal dorsal horn and dorsal root ganglia by Mas-related gene (Mrg) receptors in a rat model of spinal nerve injury

“…This feature can be of clinical interest as targeting these receptors would mainly impact nociception. It has been demonstrated that MrgC receptors are upregulated following peripheral nerve injury (He, et al, 2014a) and activation of these receptors inhibits neuropathic pain by the inhibition of synaptic neurotransmission between primary afferents and dorsal horn neurons (He, et al, 2014b;Li, et al, 2014). The present study investigated whether MrgC receptors could reverse nerve injury-induced upregulation of A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 pronociceptive mediators and activation of astrocytes in the spinal dorsal horn and phenotypic switching of DRG neurons.…”

The inhibition of high-voltage-activated calcium current by activation of MrgC11 involves phospholipase C-dependent mechanisms

“…Intrathecal administration of agonists to MrgC (mouse MrgC11, rat homolog rMrgC) produces analgesic effects in rodent models of inflammatory and neuropathic pain(Chen et al, 2006; Guan et al, 2010a; Jiang et al, 2013; He et al, 2014b). Recent studies have begun to reveal cellular mechanisms that may underlie MrgC agonist-induced analgesia in animal models of these pain types (Jiang et al, 2013; Wang et al, 2013; Li et al, 2014). …”