Decreased sensory nerve excitation and bone pain associated with mouse Lewis lung cancer in TRPV1-deficient mice

Wakabayashi, Hiroki; Wakisaka, Satoshi; Hiraga, Toru; Hata, Kenji; Nishimura, Riko; Tominaga, Makoto; Yoneda, Toshiyuki

doi:10.1007/s00774-017-0842-7

Cited by 57 publications

(39 citation statements)

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“…Interestingly, the levels of tumour‐infiltrating neutrophils and eosinophils, as well as sensory neuron innervation, correlate with the severity of pain and itch experienced by patients with melanoma . Finally, the pharmacological inhibition and genetic depletion of TRPV1 + neurons support an essential role in these fibres in transmitting bone cancer‐induced pain. Thus, in a mouse model of this disease, blocking CB2R dampens morphine tolerance .…”

Section: Endogenous Triggersmentioning

confidence: 95%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro‐immune interplay is still ill‐defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH1‐mediated immunity but also as drivers of TH2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide‐ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

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Section: Endogenous Triggersmentioning

confidence: 95%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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“…19 Since the newer TRPV1 antagonist(s) were not commercially available during the execution of our experiments, we used an older (less specific) TRPV1 antagonist peptide called L-R 4 W 2 to determine the therapeutic potential of TRPV1 antagonism in our model. To diminish any potential systemic side effects of L-R 4 W 2 , the TRPV1 antagonist was delivered intraurethrally into the prostate of mice with established pelvic tactile allodynia at days 20,22,24,26,28,30,32, and 34 ( Figure 6A). Notably, our data confirmed that treatment with L-R 4 W 2 reversed the level of pelvic tactile allodynia in mice with EAP after initial infusion at day 20 ( Figure 6B).…”

Section: Trpv1 Antagonist Blunts Persistent Pelvic Tactile Allodyniamentioning

confidence: 99%

“…Despite the mixed research results on TRPV1 compounds, studies have demonstrated that TRPV1‐deficient mice show decreased pain in models of arthritis, bone cancer, and inflammatory bowel disease . However, it is unclear whether TRPV1 plays a role in the mouse model of CP/CPPS.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the mixed research results on TRPV1 compounds, studies have demonstrated that TRPV1-deficient mice show decreased pain in models of arthritis, bone cancer, and inflammatory bowel disease. [27][28][29] However, it is unclear whether TRPV1 plays a role in the mouse model of CP/CPPS. Therefore, this study will (a) explore the role of TRPV1 in the maintenance of pelvic tactile allodynia, (b) establish the relevance of TRPV1 to prostate inflammation and mast cell activation, and (c) determine whether blocking the TRPV1 channel reduces pelvic tactile allodynia in mice with EAP.…”

Section: Introductionmentioning

confidence: 99%

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TRPV1 in experimental autoimmune prostatitis

et al. 2019

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Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS. Methods Male C57BL/6J (B6) and TRPV1 knockout (TRPV1 KO) mice (5‐7 weeks old) were used to study the development of pelvic allodynia in a murine model of CP/CPPS called experimental autoimmune prostatitis (EAP). The prostate lobes, dorsal root ganglia (DRG), and spinal cord were excised at day 20. The prostate lobes were assessed for inflammation, TRPV1 expression, and mast cell activity. DRG and spinal cord, between the L6‐S4 regions, were analyzed to determine the levels of phosphorylated ERK1/2 (p‐ERK 1/2). To examine the therapeutic potential of TRPV1, B6 mice with EAP received intraurethral infusion of a TRPV1 antagonist at day 20 (repeated every 2 days) and pelvic pain was evaluated at days 20, 25, 30, and 35. Results Our data showed that B6 mice with EAP developed pelvic tactile allodynia at days 7, 14, and 20. In contrast, TRPV1 KO mice with EAP do not develop pelvic tactile allodynia at any time point. Although we observed no change in the levels of TRPV1 protein expression in the prostate from B6 mice with EAP, there was evidence of significant inflammation and elevated mast cell activation. Interestingly, the prostate from TRPV1 KO mice with EAP showed a lack of mast cell activation despite evidence of prostate inflammation. Next, we observed a significant increase of p‐ERK1/2 in the DRG and spinal cord from B6 mice with EAP; however, p‐ERK1/2 expression was unaltered in TRPV1 KO mice with EAP. Finally, we confirmed that intraurethral administration of a TRPV1 antagonist peptide reduced pelvic tactile allodynia in B6 mice with EAP after day 20. Conclusions We demonstrated that in a murine model of CP/CPPS, the TRPV1 channel is key to persistent pelvic tactile allodynia and blocking TRPV1 in the prostate may be a promising strategy to quell chronic pelvic pain.

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“…1, C Opioid is a mainstay treatment for cancer pain, which often becomes unbearable after tumor metastasis to bone tissue 15 . We assessed whether morphine would attenuate cancer pain in WT and KO mice in bone cancer pain 16 . Inoculation of Lewis lung cancer cells into tibia resulted in severe cancer pain, as indicated by reductions in mechanical and thermal pain thresholds.…”

mentioning

confidence: 99%

Morphine analgesia and μ opioid receptor signaling require programed death protein 1

Wang

Jiang

et al. 2019

Preprint

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Opioids such as morphine produce analgesia via mu opioid receptor (MOR), but opioid receptor signaling is not fully understood. Here we report that morphine analgesia and MOR signaling require neuronal Programmed cell death protein-1 (PD-1). We found that morphine-induced antinociception following systemic or intrathecal injection was compromised in Pd1 −/− mice. Morphine analgesia was also abrogated in wild-type mice after treatment with Nivolumab, a clinically used anti-PD-1 monoclonal antibody. Morphine produced analgesia by suppressing calcium currents in DRG neurons and excitatory synaptic transmission in spinal cord neurons, but strikingly, both actions were impaired by PD-1 blockade. In a mouse model of bone cancer, the antinociceptive action of systemic morphine was compromised in Pd1 −/− mice. Finally, PD-L1 and morphine produce synergistic analgesia. Our findings demonstrate that PD-1 also acts as a neuro checkpoint inhibitor and mediates opioid-induced analgesia and MOR signaling in neurons.

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Decreased sensory nerve excitation and bone pain associated with mouse Lewis lung cancer in TRPV1-deficient mice

Cited by 57 publications

References 50 publications

Profiling of how nociceptor neurons detect danger – new and old foes

Profiling of how nociceptor neurons detect danger – new and old foes

TRPV1 in experimental autoimmune prostatitis

Morphine analgesia and μ opioid receptor signaling require programed death protein 1

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