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Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70-0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.
Learn More >Non-medical prescription opioid use (NMPOU) is at the heart of the opioid epidemic in the United States. Although chronic opioid use is commonly accompanied by deficits in social functioning, little is known about the impact of chronic NMPOU on social cognitive functions. Social neuroscience models suggest that empathy activates similar or even equivalent neural structures as those underpinning the first-hand experience in that emotional state (e.g., pain). Therefore, we measured subjective and psychophysiological responses during an empathy-for-pain task in 23 individuals with NMPOU, objectively confirmed by hair and urine testing, and compared them with 29 opioid-naïve healthy controls. NMPOU individuals showed lower other-related and self-related unpleasantness ratings when seeing others in pain than controls. No differences between the control and NMPOU group were found in skin conductance responses and heart rate variability (HRV) assessed by root mean square of successive differences (RMSSD) in response to the task. However, RMSSD-HRV was strongly negatively correlated with self-related unpleasantness and craving in the NMPOU group. A subsequent mediation analysis showed a total effect of RMSSD-HRV on self-related unpleasantness with no mediation of craving. This indicates that stronger emotion regulation indexed by high RMSSD-HRV might have downregulating effects on sharing others' pain in NMPOU individuals but not in healthy controls, which was further accompanied by decreased ratings of personal distress and empathetic concern. These results contribute to a better understanding of social functioning in chronic opioid users, suggesting adequate emotion regulation and empathy trainings as therapeutic targets for future interventions of opioid use disorders and long-term pain treatment with opioids.
Learn More >Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABA and GABA receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABA receptor-mediated inhibition. GABA receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABA receptor-mediated inhibition. Administration of the GABA receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition.
Learn More >Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy.
The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (Ca2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly ( < 0.0001, < 0.0001, and < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA ( < 0.0001, < 0.01, and < 0.05, respectively), and 300 nM and 100 nM GVIA ( < 0.0001 and < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.
Learn More >Mas-related G coupled receptors (Mrgprs) are a superfamily of receptors expressed in sensory neurons that are known to transmit somatic sensations from the skin to the central nervous system. Interestingly, Mrgprs have recently been implicated in sensory and motor functions of mucosal-associated neuronal circuits. The gastrointestinal and pulmonary tracts are constantly exposed to noxious stimuli. Therefore, it is likely that neuronal Mrgpr signaling pathways in mucosal tissues, akin to their family members expressed in the skin, might relay messages that alert the host when mucosal tissues are affected by damaging signals. Further, Mrgprs have been proposed to mediate the cross-talk between sensory neurons and immune cells that promotes host-protective functions at barrier sites. Although the mechanisms by which Mrgprs are activated in mucosal tissues are not completely understood, these exciting studies implicate Mrgprs as potential therapeutic targets for conditions affecting the intestinal and airway mucosa. This review will highlight the central role of Mrgpr signaling pathways in the regulation of homeostasis at mucosal tissues.
Learn More >Musculoskeletal pain is a challenging condition for both patients and physicians. Many adults have experienced one or more episodes of musculoskeletal pain at some time of their lives, regardless of age, gender, or economic status. It affects approximately 47% of the general population. Of those, about 39-45% have long-lasting problems that require medical consultation. Inadequately managed musculoskeletal pain can adversely affect quality of life and impose significant socioeconomic problems. This manuscript presents a comprehensive review of the management of chronic musculoskeletal pain. It briefly explores the background, classifications, patient assessments, and different tools for management according to the recently available evidence. Multimodal analgesia and multidisciplinary approaches are fundamental elements of effective management of musculoskeletal pain. Both pharmacological, non-pharmacological, as well as interventional pain therapy are important to enhance patient's recovery, well-being, and improve quality of life. Accordingly, recent guidelines recommend the implementation of preventative strategies and physical tools first to minimize the use of medications. In patients who have had an inadequate response to pharmacotherapy, the proper use of interventional pain therapy and the other alternative techniques are vital for safe and effective management of chronic pain patients.
Learn More >The COVID-19 pandemic has had a disproportionate impact on vulnerable populations, including individuals with chronic pain. We examined associations between geographical variations in COVID-19 infection rates, stress and pain severity, and investigated factors associated with changes in pain status and psychological distress among individuals living with chronic pain during the pandemic.
Learn More >Rat somatosensory neurons express junctional protein, junctophilin-4 (JPH4) JPH4 is necessary for the formation of store operated Ca entry (SOCE) complex at the junctions between plasma membrane and endoplasmic reticulum in these neurons. Knockdown of JPH4 impairs endoplasmic reticulum Ca store refill and junctional Ca signalling in sensory neurons. In vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly attenuated experimentally-induced inflammatory pain in rats. Junctional nanodomain Ca signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.
Learn More >Increased activity and excitability (sensitisation) of a series of molecules including the transient receptor potential ion channel, vanilloid subfamily, member 1 (TRPV1) in pain-sensing (nociceptive) primary sensory neurons are pivotal for developing pathological pain experiences in tissue injuries. TRPV1 sensitisation is induced and maintained by two major mechanisms; post-translational and transcriptional changes in TRPV1 induced by inflammatory mediators produced and accumulated in injured tissues, and TRPV1 activation-induced feed-forward signalling. The latter mechanism includes synthesis of TRPV1 agonists within minutes, and upregulation of various receptors functionally linked to TRPV1 within a few hours, in nociceptive primary sensory neurons. Here, we report that a novel mechanism, which contributes to TRPV1 activation-induced TRPV1-sensitisation within ~ 30 min in at least ~ 30% of TRPV1-expressing cultured murine primary sensory neurons, is mediated through upregulation in cyclooxygenase 2 (COX2) expression and increased synthesis of a series of COX2 products. These findings highlight the importance of feed-forward signalling in sensitisation, and the value of inhibiting COX2 activity to control pain, in nociceptive primary sensory neurons in tissue injuries.
Learn More >Pain is common among adults with traumatic brain injury (TBI), yet little data exists regarding prevalence of opioid use in this population. The objective of this retrospective cohort study was to evaluate the association between lifetime TBI exposure, opioid use, and pain in a nationally-representative sample of 1,022 adults aged 50+ who participated in the Health and Retirement Study (HRS). Our primary exposure was lifetime TBI history measured via the Ohio State University TBI Identification Method. We evaluated three alternate TBI exposures (years since most recent TBI, age at first TBI, and number of lifetime TBIs) in sensitivity analyses. We evaluated two outcomes: recent opioid medication use, and moderate-to-severe pain measured over two HRS waves. We classified three pain groups (persistent, intermittent, and no pain). Prevalence of opioid use among individuals with and without TBI were 19.7% and 13.6%, respectively. After adjustment for age, sex, and race, individuals with TBI had a 52% increased risk for opioid use compared to individuals without TBI (RR=1.52, 95% CI: 1.11, 2.04). Individuals with recent TBI (1-10 years ago), first TBI after age 40+, and 2+ lifetime TBIs had greatest risk for opioid use. Compared to individuals without TBI, individuals with TBI had 4.9-times increased odds for persistent versus no pain, and 1.9-times increased odds of intermittent versus no pain. Persistent pain among adults with lifetime TBI is elevated compared to the general population, which may contribute to increased opioid use among persons with TBI, particularly those with recent injuries or multiple lifetime TBIs.
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