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The trigemino-vascular system (TVS) plays a key role in migraine pathophysiology. Glial cells are abundant in the TVS system and mainly in the trigeminal ganglion. S100B protein is a calcium-binding protein, found in the cytoplasm of glial cells in the central nervous system, which is released in response to inflammatory stimuli. Previous works analyzing S100B in migraineurs have offered contradictory results.
Learn More >Although previous reports described the beneficial role of angiotensin-converting enzyme inhibitors (ACE-Is) or AT1 receptor blockers (ARBs) in attenuating neuropathic pain (NP), no study has yet explored the exact underlying mechanisms, as well as the superiority of using centrally versus peripherally acting renin-angiotensin-aldosterone system (RAAS) drugs in NP. We investigated the effects of 14 days of treatment with centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) acting ARBs and ACE-Is, respectively, in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats. We also compared these with the effects of pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (NFкB, TNF-α, COX-2, PGE2, and bradykinin), oxidative stress markers (NADPH oxidase and catalase), STAT3 activation, levels of phosphorylated P38-MAPK, ACE, AT1 receptor (AT1R), and AT2 receptor (AT2R), as well as histopathological features, were assessed in the brainstem and sciatic nerve. CCI resulted in clear pain-related behavior along with increased levels of inflammatory and oxidative stress markers, and STAT3 activity, as well as increased levels of phosphorylated P38-MAPK, ACE, AT1R, and AT2R, along with worsened histopathological findings in both the brainstem and sciatic nerve. ARBs improved both animal behavior and all measured parameters in CCI rats and were more effective than ACE-Is. At the tested doses, centrally acting ARBs or ACE-Is were not superior to the peripherally acting drugs of the same category. These findings suggest that ARBs (centrally or peripherally acting) are an effective treatment modality for NP.
Learn More >Chronic pain is a serious debilitating condition that affects ∼20% of the world's population. Currently available drugs fail to produce effective pain relief in many patients and have dose-limiting side effects. Several voltage-gated sodium (NaV) and calcium (CaV) channels are implicated in the etiology of chronic pain, particularly NaV1.1, NaV1.3, NaV1.7-NaV1.9, CaV2.2 and CaV3.2. Numerous NaV and CaV modulators have been described, but with few exceptions, they display poor potency and/or selectivity for pain-related channel subtypes. Here we report the discovery and characterization of two novel tarantula-venom peptides (Tap1a and Tap2a) isolated from Theraphosa apophysis venom that modulate the activity of both NaV and CaV3 channels. Tap1a and Tap2a inhibited on-target NaV and CaV3 channels at nanomolar to micromolar concentrations and displayed moderate off-target selectivity for NaV1.6 and weak affinity for NaV1.4 and NaV1.5. The most potent inhibitor, Tap1a, nearly ablated neuronal mechanosensitivity in afferent fibers innervating the colon and the bladder, with in vivo intracolonic administration reversing colonic mechanical hypersensitivity in a mouse model of irritable bowel syndrome. These findings suggest that targeting a specific combination of NaV and CaV3 subtypes provides a novel route for treatment of chronic visceral pain.
Learn More >Opioid dose escalation to effectively control pain is often linked to the current prescription opioid abuse epidemic. This creates social as well as medical imperatives to better understand the mechanistic underpinnings of opioid tolerance to develop interventions that minimize it, thereby maximizing the analgesic effectiveness of opioids. Profound opioid analgesic tolerance can be observed in the absence of mu-opioid receptor (MOR) downregulation, aggregate MOR G protein uncoupling, and MOR desensitization, in the absence of impaired G protein coupled receptor kinase phosphorylation, arrestin binding, or endocytosis. Thus, we have explored alternative biochemical sequelae that might better account for opioid analgesic tolerance. Our findings indicate that substantial plasticity among upstream and downstream components of opioid receptor signaling and the emergence of alternative signaling pathways are major contributors to opioid analgesic tolerance. An exemplar of this plasticity is our findings that chronic morphine upregulates the MOR variants MOR-1B2 and MOR-1C1 and phosphorylation of their C-terminal sites not present in MOR-1, events causally associated with the chronic morphine-induced shift in MOR G protein coupling from predominantly GG inhibitory to G-stimulatory adenylyl cyclase signaling. The unique feature(s) of these variants that underlies their susceptibility to adapting to chronic morphine by altering the nature of their G protein coupling reveals the richness and pliability of MOR signaling that is enabled by generating a wide diversity of MOR variants. Furthermore, given differential anatomical expression patterns of MOR variants, MOR splice variant-dependent adaptations to chronic morphine could enable mechanistic underpinnings of tolerance and dependence that are CNS region- and cell-specific.
Learn More >Chronic pain (CP) was associated with impaired cognitive performance in several cross-sectional studies conducted in older adults; however, fewer longitudinal studies assessed this link which remains still debated. With a prospective design, the present analysis was aimed at evaluating the relationship between CP and the change in several tests assessing memory, attention, verbal fluency and processing speed. The study population was selected from the PAQUID study, a cohort of community dwellers aged 65 and over; 693 subjects receiving a pain assessment were included. CP was evaluated using a questionnaire administered at 3-year follow-up. Cognitive performances were assessed every 2-3 years between 3 and 15 years assessing general cognition (MMSE), verbal and visual memory (word paired associate test and Benton test) attention and speed processing (Wechsler DSST, Zazzo's cancellation task) language skills and executive functions (Isaacs set test). The link between CP and the change in cognitive function was assessed with latent process mixed models controlled for age, gender, education, comorbidities, depression and analgesic drugs. The association between CP and each of the cognitive scores was then tested with the same procedure. A significant relationship was observed between CP and poorer 15-year scores on global cognitive performance (p=0.004), and specifically DSST (p=0.002) associated with a higher slope of decline (p=0.02). CP is associated with higher cognitive decline, in particular in processing speed. This result reinforces the importance of actively treating CP with pharmacological and non-pharmacological strategies to prevent its consequences, including cognitive consequences.
Learn More >This review examines recent (2016 onwards) neuroscientific findings on the mechanisms supporting mindfulness-associated pain relief. To date, its clear that mindfulness lowers pain by engaging brain processes that are distinct from placebo and vary across meditative training level. Due to rapid developments in the field of contemplative neuroscience, an update review on the neuroimaging studies focused on mindfulness, and pain is merited.
Learn More >Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (e.g. conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experiment sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. Additionally, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations and placebo response emphasizing the need to consider sex as a biological variable when placebo outcomes are parts of drug development trials and in pain management.
Learn More >Frequent exposure to patient distress is associated with higher prevalence of clinician distress and symptoms of burnout. Patients with chronic pain often present with high levels of emotional distress. The current study examined the prevalence of burnout symptoms among a multidisciplinary sample of pain clinicians in Australia, the relationship between clinician confidence managing emotions and symptoms of burnout, and clinicians' perspectives on sources of stress and wellbeing at work. One hundred and seventy-six clinicians from 58 multidisciplinary pain clinics across Australia completed a survey including the 22-item Maslach Burnout Inventory, a measure of clinician confidence managing patient emotions and their own emotions, and open-ended questions probing clinician perspectives on sources of stress and wellbeing at work. High levels of emotional exhaustion and depersonalisation were reported by 21.6% and 14.2% of respondents, respectively. These burnout symptoms were predicted by clinician confidence managing their own emotions. Low levels of personal accomplishment were reported by 18.8% of respondents and were predicted by clinician confidence managing patients' emotions. Consistent with these quantitative findings, qualitative data revealed that emotionally challenging patient encounters were common sources of stress. Working with a multidisciplinary team and supportive relationships with colleagues were commonly reported sources of clinician wellbeing. The results of this study are discussed in light of previous reports of burnout in pain medicine physicians. Implications for clinician training in pain management and the prevention of burnout in pain clinicians are discussed.
Learn More >Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon is poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared to Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared to SD counterparts. Equivalent plasma morphine levels in the two rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal grey (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of vlPAG, namely the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.
Learn More >A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G activator with minimal β-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates.
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