scholarly journals TRPV1 regulates opioid analgesia during inflammation

2018 ◽  
Author(s):  
Lilian Basso ◽  
Reem Aboushousha ◽  
Churmy Yong Fan ◽  
Mircea Iftinca ◽  
Helvira Melo ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Inflammatory Pain ◽  
Nuclear Translocation ◽  
Opioid Analgesic ◽  
Mapk Signaling ◽  
Opioid Analgesia ◽  
Signaling Mechanism ◽  
Pain Model ◽  
Trpv1 Channels ◽  
Peripheral Opioid Analgesia

AbstractAcute inflammation in humans or mice enhances the analgesic properties of opioids. However, the inflammatory transducers that prime opioid receptor signaling in nociceptors are unknown. We found that TRPV1−/− mice are insensitive to peripheral opioid analgesia in an inflammatory pain model. We report that TRPV1 channel activation drives a MAPK signaling pathway accompanied by the shuttling of β-arrestin2 to the nucleus. This shuttling in turn prevents: β-arrestin2-receptor recruitment, subsequent internalization of agonist-bound mu opioid receptor (MOR), and suppression of DAMGO-induced inhibition of N-type calcium current observed upon desensitization. Consequently, inflammation-induced activation of TRPV1 preserves opioid analgesic potency in a mouse model of opioid receptor desensitization. Overall, our work reveals a TRPV1-mediated signaling mechanism, involving β-arrestin2 nuclear translocation, that underlies the peripheral opioid control of inflammatory pain. Our data single out TRPV1 channels as modulators of opioid analgesia.

scholarly journals TRPV1 promotes opioid analgesia during inflammation

2019 ◽  
Vol 12 (575) ◽  
pp. eaav0711 ◽  
Author(s):  
Lilian Basso ◽  
Reem Aboushousha ◽  
Churmy Yong Fan ◽  
Mircea Iftinca ◽  
Helvira Melo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Opioid Receptor ◽  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Nuclear Translocation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Opioid Analgesia ◽  
Transient Receptor Potential Vanilloid ◽  
Receptor Desensitization

Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-arrestin2 in turn prevented its recruitment to the μ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund’s adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of β-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1–β-arrestin2 axis may thus contribute to the transition from acute to chronic pain.

scholarly journals Enhanced Peripheral Analgesia Using Virally Mediated Gene Transfer of the μ-Opioid Receptor in Mice

2008 ◽  
Vol 108 (2) ◽  
pp. 305-313 ◽  
Author(s):  
Guohua Zhang ◽  
Husam Mohammad ◽  
Brad D. Peper ◽  
Srinivasa Raja ◽  
Steven P. Wilson ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Analgesia ◽  
Complementary Dna ◽  
Innovative Strategy ◽  
Peripheral Analgesia ◽  
Peripheral Opioid Analgesia ◽  
Simplex Virus

Background The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the mu-opioid receptor (muOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. Methods Cutaneous inoculation with herpes simplex virus containing muOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of muOR in primary afferents. The effects of altered muOR levels on peripheral analgesia were then examined. Results At 4 weeks after SGAMOR and SGMOR infection, decreased and increased muOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in muOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. Conclusions This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.

Substance P enhances NF-κB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways

2008 ◽  
Vol 294 (6) ◽  
pp. C1586-C1596 ◽  
Author(s):  
Jia Sun ◽  
Raina Devi Ramnath ◽  
Liang Zhi ◽  
Ramasamy Tamizhselvi ◽  
Madhav Bhatia
Keyword(s):  
Substance P ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Nuclear Translocation ◽  
Mapk Signaling ◽  
Chemokine Production ◽  
Signaling Mechanism ◽  
Monocyte Chemoattractant Protein 1 ◽  
Murine Macrophages ◽  
Neurokinin 1

The neuropeptide substance P (SP), as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells, including macrophages. In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. We studied the effect on the murine monocyte/macrophage cell line RAW 264.7 as well as isolated primary macrophages. Our data show that SP, at nanomolar concentrations, elicited selective chemokine production from murine macrophages. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Furthermore, SP treatment strongly induced the classic pathway of IκB-dependent NF-κB activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-κB p65 and NF-κB-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-κB activation.

scholarly journals Purinergic ATP triggers moxibustion-induced local anti-nociceptive effect on inflammatory pain model

2021 ◽  
Author(s):  
Hai-Yan Yin ◽  
Ya-Peng Fan ◽  
Juan Liu ◽  
Dao-Tong Li ◽  
Jing Guo ◽  
...  
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Intramuscular Injection ◽  
High Performance ◽  
Atp Hydrolysis ◽  
Purinergic Signalling ◽  
Pain Model ◽  
Speed Up

AbstractPurinergic signalling adenosine and its A1 receptors have been demonstrated to get involved in the mechanism of acupuncture (needling therapy) analgesia. However, whether purinergic signalling would be responsible for the local analgesic effect of moxibustion therapy, the predominant member in acupuncture family procedures also could trigger analgesic effect on pain diseases, it still remains unclear. In this study, we applied moxibustion to generate analgesic effect on complete Freund’s adjuvant (CFA)-induced inflammatory pain rats and detected the purine released from moxibustioned-acupoint by high-performance liquid chromatography (HPLC) approach. Intramuscular injection of ARL67156 into the acupoint Zusanli (ST36) to inhibit the breakdown of ATP showed the analgesic effect of moxibustion was increased while intramuscular injection of ATPase to speed up ATP hydrolysis caused a reduced moxibustion-induced analgesia. These data implied that purinergic ATP at the location of ST36 acupoint is a potentially beneficial factor for moxibustion-induced analgesia.

scholarly journals TGF-  and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions

2014 ◽  
Vol 34 (15) ◽  
pp. 5385-5395 ◽  
Author(s):  
A. Lantero ◽  
M. Tramullas ◽  
F. Pilar-Cuellar ◽  
E. Valdizan ◽  
R. Santillan ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Analgesia ◽  
Receptor Signaling ◽  
Signaling Crosstalk ◽  
Pathological Pain

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

2015 ◽  
Vol 53 (11) ◽  
pp. 1621-1627 ◽  
Author(s):  
Sonja Vuckovic ◽  
Dragana Srebro ◽  
Katarina Savic Vujovic ◽  
Milica Prostran
Keyword(s):  
Magnesium Sulfate ◽  
Inflammatory Pain ◽  
Pain Model ◽  
Mk 801 ◽  
Antinociceptive Effects

scholarly journals Anti-Inflammatory Activity of Populus deltoides Leaf Extract via Modulating NF-κB and p38/JNK Pathways

2018 ◽  
Vol 19 (12) ◽  
pp. 3746 ◽  
Author(s):  
Ye Jeong ◽  
Mi-Young Lee
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Leaf Extract ◽  
Populus Deltoides ◽  
Nuclear Translocation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
No Production ◽  
Anti Inflammatory

Populus deltoides, known as eastern cottonwood, has been commonly used as a medicinal plant. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory activity of P. deltoides leaf extract (PLE). PLE effectively inhibited the expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, but not that of cyclooxygenase-2 (COX-2) and prostaglandin E2. Proinflammatory tumor necrosis factor alpha (TNF-α) levels were also reduced by the extract. PLE inhibited the phosphorylation of nuclear factor-kappa B (NF-κB) and inhibitor of Kappa Bα (IκBα), and blunted LPS-triggered enhanced nuclear translocation of NF-κB p65. In mitogen-activated protein kinase (MAPK) signaling, PLE effectively decreased the phosphorylation of p38 and c-Jun N-terminal protein kinase (JNK), but not of extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these results suggest that anti-inflammatory activity of P. deltoides leaf extract might be driven by iNOS and NO inhibition mediated by modulation of the NF-κB and p38/JNK signaling pathways.

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