Metabotropic Glutamate Receptor 5 Modulates Nociceptive Plasticity via Extracellular Signal-Regulated Kinase–Kv4.2 Signaling in Spinal Cord Dorsal Horn Neurons

Abstract

Metabotropic glutamate receptors (mGluRs) play important roles in the modulation of nociception. The group I mGluRs (mGlu1 and mGlu5) modulate nociceptive plasticity via activation of extracellular signal-regulated kinase (ERK) signaling. We reported recently that the K ϩ channel Kv4.2 subunit underlies A-type K ϩ currents in the spinal cord dorsal horn and is modulated by the ERK signaling pathway. Kv4.2-mediated A-type currents are important determinants of dorsal horn neuronal excitability and central sensitization that underlies hypersensitivity after tissue injury. In the present study, we demonstrate that ERK-mediated phosphorylation of Kv4.2 is downstream of mGlu5 activation in spinal cord dorsal horn neurons. Activation of group I mGluRs inhibited Kv4.2-mediated A-type K ϩ currents and increased neuronal excitability in dorsal horn neurons. These effects were mediated by activation of mGlu5, but not mGlu1, and were dependent on ERK activation. Analysis of Kv4.2 phosphorylation site mutants clearly identified S616 as the residue responsible for mGlu5-ERK-dependent modulation of A-type currents and excitability. Furthermore, nociceptive behavior induced by activation of spinal group I mGluRs was impaired in Kv4.2 knock-out mice, demonstrating that, in vivo, modulation of Kv4.2 is downstream of mGlu5 activation. Altogether, our results indicate that activation of mGlu5 leads to ERK-mediated phosphorylation and modulation of Kv4.2-containing potassium channels in dorsal horn neurons. This modulation may contribute to nociceptive plasticity and central sensitization associated with chronic inflammatory pain conditions.

Membrane-Delimited Coupling of TRPV1 and mGluR5 on Presynaptic Terminals of Nociceptive Neurons

“…org as supplemental material), suggesting marginal effects of general anesthetics on the pain behaviors observed in our behavioral study. In agreement with previous reports (Fisher and Coderre, 1998;Karim et al, 2001;Hu et al, 2007), a single intrathecal injection of 15 nmol DHPG, a selective group I mGluR (mGluR1/5) agonist, induced an immediate and robust increase in wild-type mice in the time spent either flinching, licking, or biting hindpaws or tails (*p Ͻ 0.05, **p Ͻ 0.001 vs preinjection baseline; one-way repeated-measures ANOVA followed by Bonferroni's t test) (Fig. 1 A).…”

“…However, mGluR1 and mGluR5 may have different cellular mechanisms for their nociceptive signaling. Recent reports demonstrate that mGluR5 is the predominant group I mGluR mediating DHPG-induced responses both in cultured mouse DRG neurons (Hu et al, 2002) and in spinal dorsal horn neurons (Hu et al, 2007). Our results also demonstrate that mGluR5 is highly likely to be the predominant group I mGluR on the central presynaptic terminals.…”

“…Thus, synaptic modulation of primary afferent neurons in the SG is believed to play an important role not only in acute nociceptive transmission but also in central sensitization associated with chronic pain (Lu and Perl, 2005). Recently, it has been demonstrated that mGluR5 modulates nociceptive plasticity via Kv4.2 signaling in postsyn- aptic spinal dorsal horn neurons (Hu et al, 2007). Our results suggest that mGluR5 on the central presynaptic terminals of nociceptive neurons may also play an important role for the central sensitization under pathological pain conditions by membranedelimited coupling with TRPV1.…”

“…It has been previously demonstrated that spontaneous pain responses are produced by the activation of spinal group I mGluRs (Fisher and Coderre, 1998;Karim et al, 2001;Hu et al, 2007). We first investigated whether spinal TRPV1 is associated with the spontaneous pain behavior induced by the activation of spinal group I mGluRs by using TRPV1 knock-out and wild-type mice.…”

“…Indeed, both spinal mGluR5 and TRPV1 have been demonstrated to contribute to pain hypersensitivity under pathological pain conditions (Caterina et al, 2000;Walker et al, 2001a;Zhu et al, 2005;Kanai et al, 2006). Whereas a functional role for mGluR5 in superficial dorsal horn neurons (i.e., postsynaptic neurons) has recently been demonstrated (Hu et al, 2007), relatively little is known about how presynaptic mGluR5 contributes to nociceptive synaptic transmissions in the spinal dorsal horn.…”