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In addition to motor symptoms, Parkinson's disease (PD) presents high prevalence of painful symptoms responsible for worsening quality of life of PD patients. Physical exercise can improve such painful symptoms. This study evaluated the effects of exercise on nociceptive threshold using an unilateral rat model of PD, as well as the role played by cannabinoid and opioid receptors in areas responsible for pain pathways. For PD induction, Wistar rats were injected with 6-OHDA. 15 days after, rats either remained sedentary or were forced to exercise three times a week for 40 minutes. Motor and nociceptive behaviors were evaluated through cylinder and mechanical hyperalgesia tests, respectively. The animals were euthanized for analysis of cannabinoid, cannabinoid receptor type 1 (CB1) and type 2 (CB2), and μ-opioid receptor (MOR) in the anterior cingulate cortex (ACC), periaqueductal gray matter (PAG), and thalamus areas by immunohistochemistry (IHC) and Western blotting. Our data revealed a decrease in the nociceptive threshold in both forepaws after surgery; in contrast, there was improvement in painful symptoms after the exercise protocol. For cannabinoid system there were an increase in CB2 expression in the ACC and PAG, and in CB1 levels in the PAG. And for opioid system there was an increase of MOR expression in the thalamus. Thus, modulation of those receptors by physical exercise can be an important non-pharmacological intervention to reduce painful symptoms in a rat model of PD, thus contributing to knowledge and promotion of better treatment aimed at improving the quality of life of PD patients.
Learn More >Painful diabetic neuropathy (PDN), a debilitating and progressive chronic pain condition that significantly impacts quality of life, is one of the common complications seen with long-standing diabetes mellitus. Neither pharmacological treatments nor low-frequency spinal cord stimulation (SCS) has provided significant and long-term pain relief for patients with PDN. This study aims to document the value of 10-kHz SCS in addition to conventional medical management (CMM) compared with CMM alone in patients with refractory PDN.
Learn More >Persistent post-traumatic headache (PTH) following mild traumatic brain injury (mTBI) is one of the most prominent and highly reported persistent post-concussion symptoms (PPCS). Non-pharmacologic treatments, including non-invasive neurostimulation technologies, have been proposed for use. Our objective was to evaluate headache characteristics at one-month following repetitive transcranial magnetic stimulation (rTMS) treatment in participants with PTH and PPCS. A double-blind, randomized, sham-controlled, pilot clinical trial was performed on twenty participants (18-65 years) with persistent PTH (ICHD-3) and PPCS (ICD-10). Ten sessions of rTMS therapy (10Hz, 600 pulses, 70% resting motor threshold amplitude) were delivered to the left dorsolateral prefrontal cortex (DLPFC). The primary outcome was a change in headache frequency or severity at one-month post-rTMS. Two-week long daily headache diaries and clinical questionnaires assessing function, PPCS, cognition, quality of life, and mood were completed at baseline, post-treatment, and at one-, three-, and six-months post-rTMS. A two-way (treatment x time) mixed ANOVA indicated a significant overall time effect for average headache severity [F(3,54)= 3.214, p=0.03] and a reduction in headache frequency at one-month post-treatment (#/two-weeks: REAL -5.2 (SD=5.8), SHAM -3.3 (SD=7.7). Secondary outcomes revealed an overall time interaction for headache impact, depression, post-concussion symptoms, and quality of life. There was a significant reduction in depression rating in the REAL group between baseline and one-month post-treatment, with no change in the SHAM group (PHQ-9; REAL -4.3 (SD=3.7, p=0.020), SHAM -0.7 (SD=4.7, p=1.0), Bonferroni corrected). In the REAL group, 60% returned to work while only 10% returned in the SHAM group (p=0.027). This pilot study demonstrates an overall time effect on headache severity, functional impact, depression, PPCS, and quality of life following rTMS treatment in participants with persistent PTH, however, findings were below clinical significance thresholds. There was a 100% response rate, no dropouts, and minimal adverse effects, warranting a larger phase II study.
Learn More >According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model.
Learn More >Although headaches have recognized impact, there are no public policies in Brazil addressing this problem.
Learn More >Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs.
Learn More >The psychoactive plant kratom is a native plant to Southeast Asia, and its major bioactive alkaloid is mitragynine. Mitragynine exerts its analgesic properties by acting on the opioid receptors. One of its active metabolites, 7-hydroxymytraginine, is found to be 40 times more potent than mitragynine and 10 times more potent than morphine. Interestingly, current research suggests that mitragynine behaves as an atypical opioid agonist – possessing analgesic activity with less severe side effects than typical opioids. Although Thailand and Malaysia have criminalized the use, possession, growing, or selling of kratom due to its abuse potential, kratom still remains unregulated in the United States. The U.S. Drug Enforcement Agency (DEA) listed kratom as a "drug of concern" in 2008 with the intent to temporarily place mitragynine and 7-hydroxymitragynine onto Schedule I of the Controlled Substances Act. However, responses from the general public, U.S. Congress, and Kratom Alliances had the DEA retract their intent. Kratom is currently marketed in the U.S. as a dietary or herbal supplement used to treat chronic pain, anxiety, and depression with over $207 million in annual sales in the U.S. alone. Here, we will review the traditional and medicinal uses of kratom along with the synthesis of its bioactive ingredients, their pharmacology, metabolism, and structure-activity relationships. The importance in society of this currently controversial substance will also be discussed.
Learn More >Contemporary nonmalignant pain treatment algorithms commence with conservative non-invasive strategies, later progressing from minimally invasive interventions to invasive techniques or implantable devices. The most commonly used implantable devices are spinal cord stimulation (SCS) systems or targeted drug delivery (TDD) devices. Historically, SCS had been considered in advance of TDD, positioning TDD behind SCS failures. Following Institutional Review Board approval, data were extracted from electronic medical records of patients who underwent SCS trial in the Department of Pain Management at Cleveland Clinic from 1994 to 2013. The sample size was analyzed in two cohorts: those who succeeded with SCS and those who failed SCS and consequently proceeded to TDD. Univariate and multivariate analyses were performed and a predictive formula for successful outcomes was created. 945 patients were included in the cohort of which 119 (12.6%) subjects achieved adequate pain relief with TDD after failure of SCS. Gender, age, depression and primary pain diagnosis were significantly different in this subgroup. Males were 52% less likely to experience pain relief with SCS. The odds of SCS success decreased as age increased by 6% per year. Patients with comorbid depression, interestingly, were 63% more likely to succeed with SCS. A logistic model was created to predict SCS success which was used to create a predictive formula. Older male patients diagnosed with spine-related pain were more likely to benefit from TDD than SCS. This observation potentially identifies a subgroup in whom consideration for TDD in advance of SCS failure could prove more efficient and cost effective. These retrospective findings warrant prospective comparative studies to validate this derived predictive formula.
Learn More >Opioids are more commonly prescribed for chronic pain in rural settings in the USA, yet little is known about how the rural context influences efforts to improve opioid medication management.
Learn More >It has been demonstrated that smoking is associated with an increase in postoperative and chronic pain. The changes in the pain-related neural pathways responsible for these effects are unknown. Additionally, the effects of nicotine withdrawal, resulting from smoking abstinence preoperatively, has not been evaluated in terms of its impact on pain sensation. In this study, an animal model has been used to assess these effects. A rat model of long-term nicotine exposure was used. Von Frey mechanical sensory tests were performed. Western Blot and immunohistological analysis were conducted on spinal cord samples. Mechanical sensory thresholds increased in the initial period (1-3 weeks), indicating hyposensitivity. Long-term (4 -10 weeks) and under nicotine withdrawal, the mechanical sensory thresholds decreased, indicating hyperalgesia. During short-term nicotine exposure, glutamate decarboxylase 67 (GAD67), GAD65, and μ-opioid receptors (MOR) up-regulated. Beta-endorphins down-regulated. Increased γ -aminobutyric acid (GABA) and MOR appear responsible for the hyposensitivity since the GABA receptor antagonist, bicuculline and opioid receptor antagonist, naloxone decreased the mechanical thresholds of nicotine-induced hyposensitivity. In long-term nicotine exposure, the expression of GAD67, MOR, and GABA decreased. Baclofen, a derivative of GABA, reversed the hyperalgesia seen with nicotine withdrawal. Therefore, nicotine acts as an analgesic when used acutely or short-term. Long-term exposure or nicotine withdrawal (similar to smoking cessation) results in hyperalgesia. Nicotine appears to alter pain sensitivity by affecting the expression of GAD65, GAD67, MOR, endorphins, and GABA. This may partially explain the increased pain and opioid use seen in chronic smokers in the postoperative period.
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