Sonic Hedgehog Signaling Pathway: A Role in Pain Processing.

Pain, as one of the most prevalent clinical symptoms, is a complex physiological and psychological activity. Long-term severe pain can become unbearable to the body. However, existing treatments do not provide satisfactory results. Therefore, new mechanisms and therapeutic targets need to be urgently explored for pain management. The Sonic hedgehog (Shh) signaling pathway is crucial in embryonic development, cell differentiation and proliferation, and nervous system regulation. Here, we review the recent studies on the Shh signaling pathway and its action in multiple pain-related diseases. The Shh signaling pathway is dysregulated under various pain conditions, such as pancreatic cancer pain, bone cancer pain, chronic post-thoracotomy pain, pain caused by degenerative lumbar disc disease, and toothache. Further studies on the Shh signaling pathway may provide new therapeutic options for pain patients.

Knockdown of PAR2 alleviates cancer-induced bone pain by inhibiting the activation of astrocytes and the ERK pathway.

OBJECTIVE: Cancer-induced bone pain (CIBP) is a kind of pain with complex pathophysiology. Proteinase-activated receptor 2 (PAR-2) is involved in CIBP. This study explored the effects of PAR-2 on CIBP rats. METHODS: CIBP rat model was established by injecting Walker 256 rat breast cancer cells into the left tibia of female Sprague-Dawley rats and verified by tibial morphology observation, HE staining, and mechanical hyperalgesia assay. CIBP rats were injected with PAR-2 inhibitor, ERK activator, and CREB inhibitor through the spinal cord sheath on the 13th day after operation. CIBP behaviors were measured by mechanical hyperalgesia assay. On the 14th day after operation, L4-5 spinal cord tissues were obtained. PAR-2 expression, co-expression of PAR-2 and astrocyte marker GFAP, GFAP mRNA and protein levels and the ERK pathway-related protein levels were detected by Western blot, immunofluorescence double staining, RT-qPCR, and Western blot. RESULTS: CIBP rats had obvious mechanical hyperalgesia and thermal hyperalgesia from the 7th day after modeling; mechanical hyperalgesia threshold and thermal threshold were decreased; PAR-2 was increased in spinal cord tissues and was co-expressed with GFAP. PAR-2 silencing alleviated rat CIBP by inhibiting astrocyte activation. p-ERK/t-ERK and p-CREB/t-CREB levels in CIBP spinal cord were elevated, the ERK/CREB pathway was activated, while the ERK/CREB pathway was inhibited by PAR-2 silencing. The alleviating effect of PAR-2 inhibitor on hyperalgesia behaviors in CIBP rats were weakened by ERK activator, while were partially restored by CREB inhibitor. CONCLUSIONS: PAR-2 knockdown inhibited the ERK/CREB pathway activation and astrocyte activation, thus alleviating CIBP in rats.

Engagement of signaling pathways of protease-activated receptor 2 and µ-opioid receptor in bone cancer pain and morphine tolerance.

Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer. Using a rat model of bone cancer, recent findings suggest that proteinase-activated receptor 2 (PAR2) signaling pathways contribute to neuropathic pain and blocking PAR2 amplifies antinociceptive effects of systemic morphine. The purpose of our study was to examine the underlying mechanisms responsible for the role of PAR2 in regulating bone cancer-evoked pain and the tolerance of systemic morphine. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats and this evoked significant mechanical and thermal hyperalgesia. Our results showed that the protein expression of PAR2 and its downstream pathways (protein kinases namely, PKCε and PKA) and transient receptor potential vanilloid 1 (TRPV1) were amplified in the dorsal horn of the spinal cord of bone cancer rats compared to control rats. Blocking spinal PAR2 by using FSLLRY-NH2 significantly attenuated the activities of PKCε/PKA signaling pathways and TRPV1 expression as well as mechanical and thermal hyperalgesia. Also, inhibition of PKCε/PKA and TRPV1 significantly diminished the hyperalgesia observed in bone cancer rats. Additionally, blocking PAR2 enhanced the attenuations of PKCε/PKA and cyclic adenosine monophosphate induced by morphine and further extended analgesia of morphine via µ-opioid receptor (MOR). Our data revealed specific signaling pathways, leading to bone cancer pain, including the activation of PAR2, downstream PKCε/PKA, TRPV1 and resultant sensitization of MOR. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of bone cancer pain often observed in clinics.

Anti-tumor enhancement of Fei-Liu-Ping ointment in combination with celecoxib via cyclooxygenase-2-mediated lung metastatic inflammatory microenvironment in Lewis lung carcinoma xenograft mouse model.

BACKGROUND: Fei-Liu-Ping (FLP) ointment is an oral prescription medication that has been widely applied to treat lung cancer patients in China. Regulation of the metastatic microenvironment is an important therapeutic approach for prevention and treatment of tumor recurrence and metastasis. The advantage of Traditional Chinese Medicine management of lung cancer lies in the prevention of recurrence and metastasis. Our previous study has demonstrated that FLP ointment could regulate lung inflammatory microenvironment in vitro. However, the effects of FLP on the tumor microenvironment in vivo are still poorly understood. The objective of this study is to investigate the effect of FLP alone or in combination with celecoxib in the prevention of lung cancer progression by Cyclooxygenase (Cox)-2 mediated tumor inflammatory microenvironment in vivo. METHODS: 120 Lewis lung carcinoma xenograft mice were divided equally into four groups: vehicle, FLP, celecoxib, and FLP plus celecoxib. The dynamic growth of the xenografted tumors was observed using an in vivo fluorescence imaging system. Mice were sacrificed on day 14, day 21, and day 28, and tumor specimens and lung tissues were harvested to detect the metastasis-associated protein expression. RESULTS: Tumor inhibition rate was 15.4, 44.2, 47.4 % at day 14, 37.3, 34.7, 61.5 % at day 21, and 15.5, 10.3, 32.5 % at day 28 after treatment of FLP, celecoxib, and FLP plus celecoxib, respectively. Upon treatment of FLP and celecoxib together, lung metastasis rate was 30 % (8 metastatic nodules) lower than other groups. FLP inhibited Cox-2 expression in a time-dependent manner. Moreover, FLP inhibited N-cadherin, matrix metalloproteinases (MMP)-9, and Vimentin expression. Treatment of FLP in combination with celecoxib was more effective than FLP or celecoxib alone in inhibiting vascular endothelial growth factor, platelet-derived growth factor receptors ß, microsomal Prostaglandin E synthase-1, MMP-2, MMP-9, N-cadherin, and Vimentin expression, but increased E-cadherin expression. CONCLUSIONS: FLP inhibited tumor growth and metastasis in a Lewis lung xenograft mice model through the Cox-2 pathway. FLP in combination with celecoxib enhanced the antitumor growth and anti-metastasis effects. Traditional Chinese herbs combined with anti-inflammatory drugs might offer a promising strategy to prevent tumor metastasis.

PAR2-mediated upregulation of BDNF contributes to central sensitization in bone cancer pain.

BACKGROUND: Bone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain. FINDINGS: Implantation of tumor cells into the tibias induced significant thermal hyperalgesia and mechanical allodynia, and enhanced glutamatergic strength in the ipsilateral dorsal horn. Significantly increased brain-derived neurotrophic factor (BDNF) expression was detected in the dorsal horn, and blockade of spinal BDNF signaling attenuated the enhancement of glutamatergic strength, thermal hyperalgesia and mechanical allodynia in the rats with bone cancer pain. Significantly increased spinal PAR2 expression was also observed, and inhibition of PAR2 signaling ameliorated BDNF upsurge, enhanced glutamatergic strength, and thermal hyperalgesia and mechanical allodynia. Inhibition of NF-κB pathway, the downstream of PAR2 signaling, also significantly decreased the spinal BDNF expression, glutamatergic strength of dorsal horn neurons, and thermal hyperalgesia and mechanical allodynia. CONCLUSION: The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.

Naringenin alleviates bone cancer pain via NF-κB/uPA/PAR2 pathway in mice.

PURPOSE: This investigation aims to explore the protective role of Naringenin (Nar) in bone cancer pain (BCP) via TNF-α-mediated NF-κB/uPA/PAR2 pathway. METHODS: BCP model was manipulated by the injection of LL2 cells into femur of mice. The levels of TNF-α and uPA in bone tissue and serum were studied by ELISA. The expressions of PAR2, PKC-γ, PKA and TRPV1 were determined by qPCR and western blot. Levels of p-IKKß, IKKß, p-p65, p65 were determined by western blot. Levels of p-p65 and uPA in bone tissue were studied by immunohistochemistry. Behavior tests in this investigation included paw withdrawal latency (PWL) and the paw withdrawal threshold (PWT). Radiological analysis and micro-CT were used to study bone structure. The lesions of bone tissue were determined by HE staining. The Dorsal root ganglia (DRG) isolated from mice were used to determine the level of PAR2 pathway. RESULTS: Naringenin improved the BCP-induced bone damage based on the increases of BV/TV, Conn. D, BMD and BMC and the decrease of bone destruction score. Naringenin repressed the reductions of PWT and PWL in BCP mice. Naringenin decreased the levels of PAR2, PKC-γ, PKA and TRPV1 of DRG and reduced the levels of p-IKKß, p-p65, and uPA in serum and bone tissue in BCP. Importantly, naringenin suppressed the enhancement of TNF-α in serum and bone tissue in BCP mice. CONCLUSION: Naringenin alleviated pain sensitization and bone damage of mice with BCP via TNF-α-mediated NF-κB/uPA/PAR2 pathway. We demonstrated a novel pathway for anti-BCP treatment with naringenin.

Dysregulation of sphingolipid metabolism in pain.

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.

[Study on percutaneous absorption of xiaozheng zhitong cataplasm].

OBJECTIVE: To study the transdermal behavior of Xiaozheng Zhitong cataplasm in rats. METHOD: With tetrahydropalmatine as the index, the Franz diffusion cell method was adopted for the experiment. Sample content was determined with HPLC. RESULT: The transdermal permeability and the transmission rate of tetrahydropalmatine accumulated for 24 h were 20.20% and 0.744 1 microg x cm(-2) x h(-1), respectively. CONCLUSION: The transdermal behaviors of Xiaozheng Zhitong cataplasm were ideal in conformity with the zero order kinetic model.

Role of autophagy in the pathogenesis and regulation of pain.

Pain is a ubiquitous and highly concerned clinical symptom, usually caused by peripheral or central nervous injury, tissue damage, or other diseases. The long-term existence of pain can seriously affect daily physical function and quality of life and produce great torture on the physiological and psychological levels. However, the complex pathogenesis of pain involving molecular mechanisms and signaling pathways has not been fully elucidated, and managing pain remains highly challenging. As a result, finding new targets to pursue effective and long-term pain treatment strategies is required and urgent. Autophagy is an intracellular degradation and recycling process that maintains tissue homeostasis and energy supply, which can be cytoprotective and is vital in maintaining neural plasticity and proper nervous system function. Much evidence has shown that autophagy dysregulation is linked to the emergence of neuropathic pain, such as postherpetic neuralgia and cancer-related pain. Autophagy has also been connected to pain caused by osteoarthritis and lumbar disc degeneration. It is worth noting that in recent years, studies on traditional Chinese medicine have also proved that several traditional Chinese medicine monomers involve autophagy in the mechanism of pain relief. Therefore, autophagy can serve as a potential regulatory target to provide new ideas and inspiration for pain management.

A nomogram for predicting severe myelosuppression in small cell lung cancer patients following the first-line chemotherapy.

This study aimed at establishing and validating a nomogram to predict the probability of severe myelosuppression in small cell lung cancer (SCLC) patients following the first-line chemotherapy. A total of 179 SCLC cases were screened as the training group and another 124 patients were used for the validation group. Predictors were determined by the smallest Akaike's information criterion (AIC) in multivariate logistic regression analysis, leading to a new nomogram. The nomogram was validated in both training and validation groups and the predicting value was evaluated by area under the receiver operating characteristics (ROC) curve (AUC), calibration curve, and decision curve analysis (DCA). Age and tumor staging were extracted as predictors to establish a nomogram, which displayed the AUC values as 0.725 and 0.727 in the training and validation groups, respectively. This nomogram exhibited acceptable calibration curves in the two groups and its prediction added more net benefits than the treat-all scheme and treat-none scheme if the range of threshold probability in the DCA was between 15 and 60% in the training and validation groups. Therefore, the nomogram objectively and accurately predict the occurrence of severe myelosuppression in SCLC patients following the first-line chemotherapy.

[Discussion on six errors of formulas corresponding to syndromes in using the classic formulas].

The theory of formulas corresponding to syndromes is one of the characteristics of Treatise on Cold Damage and Miscellaneous Diseases (Shanghan Zabing Lun) and one of the main principles in applying classic prescriptions. It is important to take effect by following the principle of formulas corresponding to syndromes. However, some medical practitioners always feel that the actual clinical effect is far less than expected. Six errors in the use of classic prescriptions as well as the theory of formulas corresponding to syndromes are the most important causes to be considered, i.e. paying attention only to the local syndromes while neglecting the whole, paying attention only to formulas corresponding to syndromes while neglecting the pathogenesis, paying attention only to syndromes while neglecting the pulse diagnosis, paying attention only to unilateral prescription but neglecting the combined prescriptions, paying attention only to classic prescriptions while neglecting the modern formulas, and paying attention only to the formulas but neglecting the drug dosage. Therefore, not only the patients' clinical syndromes, but also the combination of main syndrome and pathogenesis simultaneously is necessary in the clinical applications of classic prescriptions and the theory of prescription corresponding to syndrome. In addition, comprehensive syndrome differentiation, modern formulas, current prescriptions, combined prescriptions, and drug dosage all contribute to avoid clinical errors and improve clinical effects.

Wnt Signaling Pathways: A Role in Pain Processing.

The wingless-related integration site (Wnt) signaling pathway plays an essential role in embryonic development and nervous system regulation. It is critically involved in multiple types of neuropathic pain (NP), such as HIV-related NP, cancer pain, diabetic neuralgia, multiple sclerosis-related NP, endometriosis pain, and other painful diseases. Wnt signaling is also implicated in the pain induced by sciatic nerve compression injury and selective spinal nerve ligation. Thus, the Wnt signaling pathway may be a potential therapeutic target for NP.

Can Src protein tyrosine kinase inhibitors be combined with opioid analgesics? Src and opioid-induced tolerance, hyperalgesia and addiction.

The clinical application of opioids may be accompanied by a series of adverse consequences, such as opioid tolerance, opioid-induced hyperalgesia, opioid dependence or addiction. In view of this issue, clinicians are faced with the dilemma of treating various types of pain with or without opioids. In this review, we discuss that Src protein tyrosine kinase plays an important role in these adverse consequences, and Src inhibitors can solve these problems well. Therefore, Src inhibitors have the potential to be used in combination with opioids to achieve synergy. How to combine them together to maximize the analgesic effect while avoiding unnecessary trouble provides a topic for follow-up research.

The nonreceptor protein tyrosine kinase Src participates in every step of cancer-induced bone pain.

Cancer-induced bone pain (CIBP) is a refractory form of pain that has a high incidence in advanced tumors. Src protein tyrosine kinase is mainly composed of six domains, with two states of automatic inhibition and activation. The modular domain allows Src to conveniently regulate by and communicate with a variety of proteins, directly or indirectly participate in each step of the CIBP process. Src is beneficial to the growth and proliferation of tumor cells, and it can promote the metastases of primary tumors to bone. In the microenvironment of bone metastasis, it mainly mediates bone resorption, activates related peripheral receptors to participate in the formation of pain signals, and may promote the generation of pathological sensory nerve fibers. In the process of pain signal transmission, it mainly mediates NMDAR and central glial cells to regulate pain signal intensity and central sensitization, but it is not limited to these two aspects. Both basic experimentation and clinical research have shown encouraging potential, providing new ideas and inspiration for the prevention and treatment of CIBP.

Efficacy and safety of TCM combined with chemotherapy for SCLC: a systematic review and meta-analysis.

BACKGROUND: Chemotherapy is the standard treatment for small cell lung cancer (SCLC), but chemotherapy resistance and adverse reactions remain major problems. Although Traditional Chinese Medicine (TCM) is wildly applied for patients with SCLC in China, the evidence of TCM in the treatment for SCLC is limited. PURPOSE: To evaluate the efficacy and safety of TCM combined with chemotherapy for patients with SCLC. METHOD: We conducted a systematic search of PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the VIP Information Database, and the Wanfang Database for randomized-controlled trials (RCTs) that are relevant. The included studies were reviewed by two investigators, with relevant data extracted independently. The effect estimate of interest was the relative risk (RR) or mean difference with 95% confidence intervals (95% CIs). RESULTS: 22 RCTs involving 1887 patients were included in this study. Compared with patients treated with chemotherapy© alone, those with Chinese herbal medicine and chemotherapy (TCM-C) had better therapeutic effects (RR = 1.295, 95% CI 1.205-1.391, P < 0.001), KPS scores (RR = 1.310, 95% CI 1.210-1.418, P < 0.001), 1-year survival rate (RR = 1.282, 95% CI 1.129-1.456, P < 0.001), 3-year survival rate (RR = 2.109, 95% CI 1.514-2.939, P < 0.001), and 5-year survival rate (RR = 2.373, 95% CI 1.227-4.587, P = 0.01). The incidence of gastrointestinal reaction (RR of = 0.786, 95% CI 0.709-0.870, P < 0.000) and bone marrow depression (RR = 0.837, 95% CI 0.726-0.965, P = 0.014) in TCM-C group were lower than that in the C group. CONCLUSION: The systematic review indicated that TCM combined with chemotherapy may improve therapeutic effect, quality of life, and prolong survival time. More large-scale and higher quality RCTs are warranted to support our findings. PROSPERO REGISTRATION NUMBER: CRD42016038016.

Norcantharidin inhibits IL-6-induced epithelial­mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells.

Epithelial-mesenchymal transition (EMT), plays a vital role in hepatocellular carcinoma (HCC) development and metastasis. Norcantharidin (NCTD; 7-oxabicyclo (2.2.1) heptane-2,3-dicarboxylic anhydride) plays anticancer roles in the regulation of tumor cell proliferation, apoptosis and migration. However, the molecular mechanism of HCC EMT and the effects of NCTD in the HCC EMT process have been either poorly elucidated or not studied. In this study, HCC EMT was induced by the treatment of IL-6 and various concentrations of NCTD (0, 30, 60 and 120 µM) were treated with HCC cell lines, HCCLM3 and SMMC-7721. We investigated the effect of NCTD on the invasion of HCC cells by using Transwell assay. Immunofluorescence staining, western blot analysis and quantitative RT-PCR were performed to evaluate the protein and mRNA expression levels of HCC cells. Here, using cell line models, our data demonstrated that interleukin 6 (IL-6) induced EMT through the JAK/STAT3/TWIST pathway in HCC. Moreover, our studies revealed that NCTD markedly inhibited IL-6-induced EMT and cell invasiveness. Signaling studies revealed that NCTD sufficiently suppressed JAK/STAT3/TWIST signaling to reverse the IL-6-promoting effects. Collectively, these data provide evidence for the use of NCTD as a potential anticancer drug in HCC metastatic patients.

Sinomenine inhibits A549 human lung cancer cell invasion by mediating the STAT3 signaling pathway.

Increasing evidence suggests that the failure of lung cancer treatment may occur as a result of tumor invasion and metastasis. Signal transducer and activator of transcription 3 (STAT3), an epithelial-mesenchymal transition-inducing transcription factor, is a key signaling molecule involved in the proliferation, apoptosis, invasion and metastasis of tumor cells. Sinomenine is an alkaloid compound with an antineoplastic potential against a variety of cancer cells. The aim of the present study was to assess the antitumor mechanisms of sinomenine in the A549 human lung cancer cell line. The results demonstrated that sinomenine manifested dose-dependent cytotoxicity and induced apoptosis in A549 cells. The protein expression of Janus kinase 2, STAT3, phosphorylated-STAT3, Snail, N-cadherin and vimentin decreased in sinomenine-treated cells, while E-cadherin protein expression increased. The regulation of STAT3, N-cadherin and E-cadherin by sinomenine was further confirmed by reverse transcription-quantitative polymerase chain reaction and immunofluorescent staining. It was demonstrated that sinomenine exerts inhibitory effects on A549 human lung cancer cell invasion, possibly through the inhibition of STAT3 signaling. These results provide a novel insight into the role of sinomenine in the treatment of non-small cell lung cancer.

New insights of nociceptor sensitization in bone cancer pain.

INTRODUCTION: Numerous studies have shown that an intact CNS is required for the conscious perception of cancer-induced bone pain (CIBP) and that changes in the CNS are clearly evident. Accordingly, the blockage of nociceptive stimulus into the CNS can effectively relieve or markedly attenuate CIBP, revealing the clinical implication of the blockage of ongoing peripheral inputs for the control of CIBP. AREAS COVERED: In this review, the heterogeneity and excitability of nociceptors in bone are covered. Furthermore, their role in initiating and maintaining CIBP is also described. EXPERT OPINION: Developing mechanistic therapies to treat CIBP is a challenge, but they have the potential to fundamentally change our ability to effectively block/relieve CIBP and increase the functional status and quality of life of patients with bone metastasis. Further studies are desperately needed at both the preclinical and clinical levels to determine whether the targets as mentioned in this review are viable and feasible for patient populations.

New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review.

Pain is an unpleasant sensory and emotional experience that is commonly associated with actual or potential tissue damage. Despite decades of pain research, many patients continue to suffer from chronic pain that is refractory to current treatments. Accumulating evidence has indicated an important role of protease-activated receptor 4 (PAR4) in the pathogenesis of inflammation and neuropathic pain. Here we reviewed PAR4 expression and activation via intracellular signaling pathways and the role of PAR4 signaling pathways in the development and maintenance of pain. Understanding PAR4 and its corresponding signaling pathways will provide insight to further explore the molecular basis of pain, which will also help to identify new targets for pharmacological intervention for pain relief.

The mechanism of µ-opioid receptor (MOR)-TRPV1 crosstalk in TRPV1 activation involves morphine anti-nociception, tolerance and dependence.

Initiated by the activation of various nociceptors, pain is a reaction to specific stimulus modalities. The µ-opioid receptor (MOR) agonists, including morphine, remain the most potent analgesics to treat patients with moderate to severe pain. However, the utility of MOR agonists is limited by the adverse effects associated with the use of these drugs, including analgesic tolerance and physical dependence. A strong connection has been suggested between the expression of the transient receptor potential vanilloid type 1 (TRPV1) ion channel and the development of inflammatory hyperalgesia. TRPV1 is important for thermal nociception induction, and is mainly expressed on sensory neurons. Recent reports suggest that opioid or TRPV1 receptor agonist exposure has contrasting consequences for anti-nociception, tolerance and dependence. Chronic morphine exposure modulates TRPV1 activation and induces the anti-nociception effects of morphine. The regulation of many downstream targets of TRPV1 plays a critical role in this process, including calcitonin gene-related peptide (CGRP) and substance P (SP). Additional factors also include capsaicin treatment blocking the anti-nociception effects of morphine in rats, as well as opioid modulation of TRPV1 responses through the cAMP-dependent PKA pathway and MAPK signaling pathways. Here, we review new insights concerning the mechanism underlying MOR-TRPV1 crosstalk and signaling pathways and discuss the potential mechanisms of morphine-induced anti-nociception, tolerance and dependence associated with the TRPV1 signaling pathway and highlight how understanding these mechanisms might help find therapeutic targets for the treatment of morphine induced antinociception, tolerance and dependence.