Group II/III Metabotropic Glutamate Receptors Exert Endogenous Activity-Dependent Modulation of TRPV1 Receptors on Peripheral Nociceptors

Carlton, Susan M.; Zhou, Sanming; Govea, R.; Du, Junying

doi:10.1523/jneurosci.6558-10.2011

Cited by 44 publications

(42 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our studies did not detect similar tonically active inhibitory mechanisms in the control of nociceptive bladder reflexes. Bladder overactivity was not altered after administration of LY341495, which induces hyperalgesia and enhances nociceptive behavior in somatic pain models (9,34). However, the drug did suppress TNS-induced inhibition of bladder overactivity.…”

Section: Discussionmentioning

confidence: 89%

“…Group II mGluR have been identified with immunohistochemical methods in the spinal cord and brain, and in small to medium size dorsal root ganglia neurons, and in cutaneous sensory nerves that coexpress TRPV1 receptors (5,7,27). Group II mGluR antagonists enhance nociceptive behavior and primary afferent firing induced by intraplantar injection of capsaicin; and a group II mGluR agonist suppressed this enhancement (9). Group II mGluR agonists are also believed to act in the spinal cord to produce analgesia (13, 34) by suppressing the release of glycine, GABA, or glutamate (35,48), whereas knockdown of group II mGluR enhances nociceptive responses (46).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Matsuta

Mally

Zhang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

(mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under ␣-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P Ͻ 0.0001) reduced bladder capacity to 26.6 Ϯ 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 Ϯ 8.3% at 2T (P Ͻ 0.01) and 80.8 Ϯ 9.2% at 4T (P ϭ 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders.neurotransmitter; neuromodulation; bladder; cat GLUTAMATERGIC NEUROTRANSMISSION involves activation of both ionotropic glutamate receptors (iGluR) and metabotropic glutamate receptors (mGluR) that consist of eight subtypes classified into group I (mGluR 1 and 5), group II (mGluR 2 and 3), and group III (mGluR 4,6,7,and 8). An interaction between iGluR and opioid receptor mechanisms is believed to be important in pain pathways, because block of ionotropic Nmethyl-D-aspartate (NMDA) receptors enhances the antinociceptive effect of morphine (an opioid receptor agonist) (14,28,36,37). Recently, the interaction between mGluR and opioid receptors has also been identified in studies of opioid-induced antinociception (15,16,29,45). Opioid-induced antinociceptive effects were enhanced by antagonists (15,16,45) and agonists (29) of group II mGluR in different types of somatic nociception. Currently, it is unknown whether this interaction between group II mGluR and opioid receptors occurs in visceral nociceptive mechanisms.Recent results from this laboratory (38) revealed that tibial nerve stimulation (TNS) inhibits bladder overactivity elicited by intravesical infusion of acetic acid (AA), which stimulates nociceptive bladder afferent nerves. This TNS-induced antinociceptive effect is completely eliminated by naloxone (an opioid...

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Matsuta

Mally

Zhang

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…Pain is associated with affective and cognitive dysfunctions as well [3;30;34], and group II mGluR agonists have antinociceptive effects at different levels of the pain neuraxis, including nociceptors [7;32], spinal dorsal horn neurons [33;45] and amygdala [1;25]. Unexpectedly, we found evidence for endogenous activation of group II mGluRs in the mPFC under normal conditions and in the arthritis pain model because a selective antagonist had facilitatory effects on synaptically evoked spiking of pyramidal cells.…”

Section: Discussionmentioning

confidence: 99%

“…In another study, LY341495 alone increased evoked EPSCs in CeA neurons in brain slices from formalin injected, but not control, mice, but this effect was not statistically significant [1]. A group II receptor antagonist (APICA) had pronociceptive effects on nociceptors in the capsaicin pain model but not under normal conditions [7]. EGLU alone had no effect on spontaneous EPSCs in spinal cord slices from neuropathic rats and sham controls [45].…”

Section: Discussionmentioning

confidence: 99%

Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex

Kiritoshi

Neugebauer

2015

Neuropharmacology

View full text Add to dashboard Cite

The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain where abnormal synaptic inhibition of mPFC pyramidal cells has been linked to cognitive deficits. Therefore, restoring normal transmission is a desirable goal. Group II metabotropic glutamate receptors mGluR 2 and 3 are highly expressed in the mPFC, modulate excitatory and inhibitory transmission, and have been targeted for the treatment of neuropsychiatric disorders, but their pain-related modulatory effects in the mPFC remain to be determined. Here we evaluated the ability of an mGluR2/3 agonist and antagonist to restore pyramidal output in an arthritis pain model. Whole-cell patch-clamp recordings were made from visually identified layer V mPFC pyramidal cells in rat brain slices. A selective group II mGluR agonist (LY379268) decreased synaptically evoked spiking in slices from normal and arthritic rats (5-6 h postinjection of kaolin/carrageenan into one knee). Effects were concentration-dependent and reversed by a selective antagonist (LY341495). LY379268 decreased monosynaptic excitatory postsynaptic currents (EPSCs) and glutamate-driven inhibitory postsynaptic currents (IPSCs) in the arthritis model. Effects on EPSCs preceded those on IPSCs and could explain the overall inhibitory effect on pyramidal output. LY379268 decreased frequency, but not amplitude, of miniature EPSCs without affecting miniature IPSCs. LY341495 by itself increased synaptically evoked spiking under normal conditions and in the pain model. We conclude that group II mGluRs act on glutamatergic synapses to inhibit direct excitatory transmission and feedforward inhibition onto pyramidal cells. Their net effect is deceased pyramidal cell output. The facilitatory effect of a group II antagonist suggests that the system may be tonically active to control pyramidal output and does not change in the pain model. Failure to release the inhibitory tone in conditions that require enhanced cortical function and output, such as pain control, could be a mechanism for the development or persistence of a disease state.

show abstract

“…Isolation of DRG neurons and fura-2 AM-based Ca 2ϩ imaging experiments were performed as described previously (Carlton et al, 2011). Rats were treated with intrathecal delivery of 30 l of TAT-T506 peptide (1 g/l) or TAT-T506A peptide (1 g/l), followed by injection of 100 l of 25% CFA into the left hindpaw.…”

Section: Methodsmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Controls TRPV1 Membrane Trafficking and the Heat Sensitivity of Nociceptors through KIF13B

Xing

Yang

et al. 2012

J. Neurosci.

View full text Add to dashboard Cite

The number of functional transient receptor potential vanilloid 1 (TRPV1) channels at the surface, especially at the peripheral terminals of primary sensory neurons, regulates heat sensitivity, and increased surface localization of TRPV1s contributes to heat hyperalgesia. However, the mechanisms for regulating TRPV1 surface localization are essentially unknown. Here, we show that cyclin-dependent kinase 5 (Cdk5), a new player in thermal pain sensation, positively regulates TRPV1 surface localization. Active Cdk5 was found to promote TRPV1 anterograde transport in vivo, suggesting a regulatory role of Cdk5 in TRPV1 membrane trafficking. TRPV1-containing vesicles bind to the forkhead-associated (FHA) domain of the KIF13B (kinesin-3 family member 13B) and are thus delivered to the cell surface. Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. Moreover, complete Freund's adjuvant (CFA) injection-induced activation of Cdk5 increased the anterograde transport of TRPV1s, contributing to the development and possibly the maintenance of heat hyperalgesia, whereas intrathecal delivery of the TAT-T506 peptide alleviated CFA-induced heat hyperalgesia in rats. Thus, Cdk5 regulation of TRPV1 membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors, and moderate inhibition of Thr-506 phosphorylation during inflammation might be helpful for the treatment of inflammatory thermal pain.

show abstract

Group II/III Metabotropic Glutamate Receptors Exert Endogenous Activity-Dependent Modulation of TRPV1 Receptors on Peripheral Nociceptors

Cited by 44 publications

References 72 publications

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation

Group II mGluRs modulate baseline and arthritis pain-related synaptic transmission in the rat medial prefrontal cortex

Cyclin-Dependent Kinase 5 Controls TRPV1 Membrane Trafficking and the Heat Sensitivity of Nociceptors through KIF13B

Contact Info

Product

Resources

About