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There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, the present series of studies reveal a novel lovastatin effect, that being as a Toll-like receptor 4 (TLR4) antagonist. Lovastatin selectively inhibits lipopolysaccharide (LPS)-induced TLR4-NF-κB activation without affecting signaling by other homologous TLRs. In vitro biophysical binding and cellular thermal shift assay (CETSA) show that lovastatin is recognized by TLR4's coreceptor myeloid differentiation protein 2 (MD-2). This finding is supported by molecular dynamics simulations that lovastatin targets the LPS binding pocket of MD-2 and lovastatin binding stabilizes the MD-2 conformation. In vitro studies of BV-2 microglial cells revealed that lovastatin inhibits multiple effects of LPS, including activation of NFkB; mRNA expression of tumor necrosis factor-a, interleukin-6 and cyclo-oxygenase 2; production of nitric oxide and reactive oxygen species; as well as phagocytic activity. Furthermore, intrathecal delivery of lovastatin over lumbosacral spinal cord of rats attenuated both neuropathic pain from sciatic nerve injury and expression of the microglial activation marker CD11 in lumbar spinal cord dorsal horn. Given the well-established role of microglia and proinflammatory signaling in neuropathic pain, these data are supportive that lovastatin, as a TLR4 antagonist, may be productively repurposed for treating chronic pain.
Learn More >Clinicians have the dilemma of prescribing opioid or nonopioid analgesics to chronic pain patients; however, the impact of pain on our endogenous µ-opioid system and how our genetic profile (specifically catechol-O-methyltransferase [] polymorphisms) impacts its activation are currently unknown. Twelve chronic temporomandibular disorder (TMD) patients and 12 healthy controls (HCs) were scanned using positron emission tomography (PET) with [C]carfentanil, a selective radioligand for µ-opioid receptors (µORs). The first 45 min of each PET measured the µOR nondisplaceable binding potential (BP) at resting state, and the last 45 min consisted of a 20-min masseteric pain challenge with an injection of 5% hypertonic saline. Participants were also genotyped for different COMT alleles. There were no group differences in µOR BP at resting state (early phase). However, during the masseteric pain challenge (late phase), TMD patients exhibited significant reductions in µOR BP (decreased [C]carfentanil binding) in the contralateral parahippocampus ( = 0.002) compared to HCs. The µOR BP was also significantly lower in TMD patients with longer pain chronicity ( < 0.001). When considering genotype and chronic pain suffering, TMD patients with the Met substitution had higher pain sensitivity and longer pain chronicity with a 5-y threshold for µOR BP changes to occur in the parahippocampus. Together, the TMD diagnosis, Met substitution, and pain chronicity explained 52% of µOR BP variance in the parahippocampus (cumulative = 52%, < 0.003, and HC vs. TMD Cohen's effect size = 1.33 SD). There is strong evidence of dysregulation of our main analgesic and limbic systems in chronic TMD pain. The data also support precision medicine by helping identify TMD patients who may be more susceptible to chronic pain sensitivity and opioid dysfunction based on their genetic profile.
Learn More >Alcoholics often experience hyperalgesia, especially during abstinence, yet the underlying cellular and molecular bases are unclear. Recent evidence suggests that 5-HT type 2 receptors (5-HTRs) at glutamatergic synapses on lateral habenula (LHb) neurons may play a critical role. We, therefore, measured paw withdrawal responses to thermal and mechanical stimuli, and alcohol intake in a rat model of intermittent drinking paradigm, as well as spontaneous glutamatergic transmission (sEPSCs), and firing of LHb neurons in brain slices. Here, we report that nociceptive sensitivity was higher in rats at 24 h withdrawal from chronic alcohol consumption than that of alcohol-naive counterparts. The basal frequency of sEPSCs and firings was higher in slices of withdrawn rats than that of Naïve rats, and 5-HT2R antagonists attenuated the enhancement. Also, an acute ethanol-induced increase of sEPSCs and firings was smaller in withdrawal than in Naïve rats; it was attenuated by 5-HTR antagonists but mimicked by 5-HTR agonists. Importantly, intra-LHb infusion of 5-HTR agonists increased nociceptive sensitivity in Naïve rats, while antagonists or 5-HT reuptake blocker decreased nociceptive sensitivity and alcohol intake in withdrawn rats. Additionally, KN-62, a CaMKII inhibitor, attenuated the enhancement of EPSCs and firing induced by acute alcohol and by 5-HTR agonist. Furthermore, intra-LHb KN-62 reduced nociceptive sensitivity and alcohol intake. Quantitative real-time PCR assay detected mRNA of 5-HT2A and 2C in the LHb. Thus adaptation in 5-HTR-CaMKII signaling pathway contributes to the hyper-glutamatergic state, the hyperactivity of LHb neurons as well as the higher nociceptive sensitivity in rats withdrawn from chronic alcohol consumption.
Learn More >Electronic (eHealth) and mobile (mHealth) technologies may be a useful adjunct to clinicians treating patients with chronic pain. The primary aim of this study was to investigate the effects of eHealth and mHealth interventions that do not require clinician contact or feedback on pain-related outcomes recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines in adults with chronic pain.
Learn More >To document the nociceptive innervation of the normal and osteoarthritic murine knee.
Learn More >Persistent opioid use is common after surgical procedures, and postoperative opioid prescribing often transitions from surgeons to primary care physicians in the months after surgery. It is unknown how surgeons currently transition these patients or the preferred approach to successful coordination of care. This qualitative study aimed to describe transitions of care for postoperative opioid prescribing and identify barriers and facilitators of ideal transitions for potential intervention targets.
Learn More >Orofacial pain syndromes encompass several clinically defined and classified entities. The focus here is on the role of clinical neurophysiologic and psychophysical tests in the diagnosis, differential diagnosis, and pathophysiological mechanisms of definite trigeminal neuropathic pain and other chronic orofacial pain conditions (excluding headache and temporomandibular disorders). The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. In addition to unambiguous painful posttraumatic or postherpetic trigeminal neuropathies, burning mouth syndrome, persistent idiopathic facial and dental pain, and trigeminal neuralgia have also been identified with neurophysiologic and quantitative sensory testing to involve the nervous system. Despite normal clinical examination, these all include clusters of patients with evidence for either peripheral or central nervous system pathology compatible with the subclinical end of a continuum of trigeminal neuropathic pain conditions. Useful tests in the diagnostic process include electroneuromyography with specific needle, neurography techniques for the inferior alveolar and infraorbital nerves, brain stem reflex recordings (blink reflex with stimulation of the supraorbital, infraorbital, mental, and lingual nerves; jaw jerk; masseter silent period), evoked potential recordings, and quantitative sensory testing. Habituation of the blink reflex and evoked potential responses to repeated stimuli evaluate top-down inhibition, and navigated transcranial magnetic stimulation allows the mapping of reorganization within the motor cortex in chronic neuropathic pain. With systematic use of neurophysiologic and quantitative sensory testing, many of the current ambiguities in the diagnosis, classification, and understanding of chronic orofacial syndromes can be clarified for clinical practice and future research.
Learn More >Opioid overdose is the leading cause of injury-related death in the United States. Several studies have shown that surgeons overprescribe opioids, and guidelines for appropriate opioid prescribing are available. Concern about patient-reported satisfaction scores may be a barrier to surgeons adopting guideline-directed prescribing.
Learn More >Newborn infants are vulnerable to procedural stress and pain exposure on the first weeks of life that represents a critical period for the development of nociceptive, sensory, emotional, and social functions. We evaluated the nociceptive behavior of adult male and female rats that were submitted to nociceptive experience in the neonatal period and the maternal behavior in the postnatal period.
Learn More >Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue, and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole-genome sequencing. When comparing FM patients with unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate-metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine-learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (receiver operating characteristic area under the curve 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in nonvisceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
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