Substance P Sensitizes P2X3 in Nociceptive Trigeminal Neurons

Park, C.K.; Bae, Joonsoo; Kim, H.Y.; Jo, Hyun Jung; Kim, Yeo Hyung; Jung, Sung Jun; Kim, J.S.; Oh, Seog Bae

doi:10.1177/0022034510377094

Cited by 32 publications

(26 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is possible that changes in P2X3 function under pathological conditions are more complex than simple upregulation or downregulation of expression at the protein level. Understanding the regulatory mechanisms of P2X3 activity is critical in elucidating its function in pain, and the modulation of P2X3 currents by intracellular pathways has recently gained attention (Giniatullin et al, 2003;Wang et al, 2007;Park et al, 2010). We previously reported that depletion of the plasma membrane-specific phospholipid phosphatidilinositol-4,5-bisphosphate (PIP 2 ) decreases P2X3 activity (Mo et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

Peleshok

Cao

et al. 2012

Mol Pharmacol

View full text Add to dashboard Cite

Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent findings suggesting the coexpression of metabotropic P2Y receptors with P2X3 implies that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with strong potential for functional interaction. Modulation of native P2X3 function by P2Y receptor activation was investigated in rat dorsal root ganglia (DRG) neurons using whole cell patch-clamp recordings. Application of the selective P2Y receptor agonist UTP decreased peak amplitudes of a,b-meATP-evoked homomeric P2X3-mediated currents, but had no effect on heteromeric P2X2/3-mediated currents. Treatment with phospholipase C inhibitor U73122 significantly reversed P2X3 current inhibition induced by UTP-sensitive P2Y receptor activation. We previously reported the modulation of P2X receptors by phospholipids in DRG neurons and injection of exogenous phosphatidylinositol-4,5-bisphosphate (PIP 2 ) fully reverses UTP-mediated regulation of P2X3 channel activity. Pharmacological as well as functional screening of P2Y receptor subtypes indicates the predominant involvement of P2Y2 receptor in P2X3 inhibition, and immunolocalization confirms a significant cellular coexpression of P2X3 and P2Y2 in rat DRG neurons. In summary, the function of P2X3 ATP receptor can be inhibited by P2Y2-mediated depletion of PIP 2 . We propose that expression of P2Y2 purinoceptor in nociceptive sensory neurons provides an homeostatic mechanism to prevent excessive ATP signaling through P2X3 receptor channels.

show abstract

Section: Introductionmentioning

confidence: 99%

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

Peleshok

Cao

et al. 2012

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…Firstly, under PTSD‐like stress conditions, substances are released from various sources that often act synergistically to cause sensitization of afferent nerves to mechanical stimuli . Secondly, P2X3 can interact with other receptors or mediators, which sensitizes other DRG neurons including capsaicin, 5‐hydroxytryptamine, bradykinin, and calcitonin gene related peptide. In addition, TRPV1 channels are activated and sensitized by ATP released during distension; this is especially prevalent in pathological stress states .…”

Section: Discussionmentioning

confidence: 99%

P2X3 receptor‐mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD‐like stress in the dorsal root ganglia of rats

Lang

et al. 2016

Neurogastroenterology Motil

View full text Add to dashboard Cite

show abstract

“…This observation prompted a possibility that both opioid-induced stimulation and inhibition of P2X This, seemingly paradoxical, conclusion is in agreement with data on the regulation of P2X 3 receptors by other metabotropic pathways. For example, activation of P2Y 2 receptors inhibits P2X 3 via PTX-sensitive G i /G o linked to PLC, whereas bradykinin and substance P receptors coupled to PTX-insensitive G q proteins stimulate P2X 3 currents through PLC/PIP 2 /DAG/PKC cascade [38][39][40]. Assuming that similar pathways are used by MORs, one could expect that PKC is involved in the stimulatory action of MORs on P3X 3 receptors as well.…”

Section: Dual Effect Of Opioids On P2x 3 Receptorsmentioning

confidence: 99%

Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones

Chizhmakov

Kulyk

Khasabova

et al. 2015

Purinergic Signalling

View full text Add to dashboard Cite

Here, we describe a molecular switch associated with opioid receptors-linked signalling cascades that provides a dual opioid control over P2X 3 purinoceptor in sensory neurones. Leu-enkephalin inhibited P2X 3 -mediated currents with IC 50~1 0 nM in~25 % of small nociceptive rat dorsal root ganglion (DRG) neurones. In contrast, in neurones pretreated with pertussis toxin leu-enkephalin produced stable and significant increase of P2X 3 currents. All effects of opioid were abolished by selective μ-opioid receptor antagonist DPhe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nonselective inhibitor naloxone, and by PLC inhibitor U73122. Thus, we discovered a dual link between purinoceptors and μ-opioid receptors: the latter exert both inhibitory (pertussis toxin-sensitive) and stimulatory (pertussis toxin-insensitive) actions on P2X 3 receptors through phospholipase C (PLC)-dependent pathways. This dual opioid control of P2X 3 receptors may provide a molecular explanation for dichotomy of opioid therapy. Pharmacological control of this newly identified facilitation/inhibition switch may open new perspectives for the adequate medical use of opioids, the most powerful pain-killing agents known today.

show abstract

Substance P Sensitizes P2X3 in Nociceptive Trigeminal Neurons

Abstract: α,β-methylene adenosine 5'-triphosphate (ATP), α,β-meATP; neurokinin-1, NK-1; single-cell reverse-transcription polymerase chain-reaction, single-cell RT-PCR; [Sar(9),Met(O(2))(11)]-substance P, Sar-substance P.

Cited by 32 publications

References 30 publications

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

P2X3 receptor‐mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD‐like stress in the dorsal root ganglia of rats

Molecular mechanism for opioid dichotomy: bidirectional effect of μ-opioid receptors on P2X3 receptor currents in rat sensory neurones

Contact Info

Product

Resources

About