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To describe the core elements of a Whole Health Primary Care Pain Education and Opioid Monitoring Program (PC-POP) and examine its effectiveness at increasing adherence to six of the Veteran Affairs/Department of Defense (VA/DoD) recommended guidelines for long-term opioid therapy (LOT) among chronic noncancer patients seen in primary care (i.e., urine drug screens [UDS], prescription drug monitoring program [PDMP] queries, informed consent, naloxone education/prescriptions, morphine equivalent daily dose [MEDD], and referrals to nonpharmacological pain interventions).
An epileptic seizure can trigger a headache during (ictal) or after (postictal) the termination of the event. Little is known about the pathophysiology of seizure-induced headaches. In the current study, we determined whether a seizure can activate nociceptive pathways that carry pain signals from the meninges to the spinal cord, and if so, to what extent and through which classes of peripheral and central neurons. To achieve these goals, we used single-unit recording techniques and an established animal model of seizure (picrotoxin) to determine the effects of epileptic seizure on the activity of trigeminovascular Aδ-, C-, wide-dynamic range, and high-threshold neurons in male and female rats. Occurrence of seizure activated 54%, 50%, 68%, and 39% of the Aδ-, C-, wide-dynamic range, and high-threshold neurons, respectively. Regardless of their class, activated neurons exhibited a twofold to fourfold increase in their firing, which started immediately (1 min) or up to 90 min after seizure initiation, and lasted as short as 10 min or as long as 120 min. Administration of lidocaine to the dura prevented activation of all neuronal classes but not the initiation or maintenance of the seizure. These findings suggest that all neuronal classes may be involved in the initiation and maintenance of seizure-induced headache, and that their activation patterns can provide a neural substrate for explaining the timing and duration of ictal and possibly postictal headaches. By using seizure, which is evident in humans, this study bypasses controversies associated with cortical spreading depression, which is less readily observed in humans.This preclinical study provides a neural substrate for ictal and postictal headache. By studying seizure effects on the activity of peripheral (C and Aδ) and central (wide dynamic range and high-threshold) trigeminovascular neurons in intact and anesthetized dura, the findings help resolve two outstanding questions about the pathophysiology of headaches of intracranial origin. The first is that abnormal brain activity (i.e., seizure) that is evident in human (unlike cortical spreading depression) gives rise to specific and selective activation of the different components of the trigeminovascular system, and the second is that the activation of all components of the trigeminovascular pathway (i.e., peripheral and central neurons) depends on activation of the meningeal nociceptors from their receptors in the dura.
To determine the prevalence of and risk factors associated with opioid use in the treatment of migraine, we examined demographics and clinical characteristics of 867 individuals who reported using opioids for the treatment of migraine.
Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics and imaging technological tools in rodent models with a view towards decoding sensory, affective and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.
Patients with nonmelanoma skin cancer (NMSC) may experience symptoms of itch and pain, which we previously reported to be associated with overall degree of inflamation . Specific mediators underlying itch and pain in NMSCs have not been studied, so immunohistochemistry was performed for mediators involved in these pathways. 60 subjects from a tissue repository were included in this study for a total of 50 histopathologically confirmed NMSCs and 10 healthy controls. Participants were asked to rank their current itch and pain intensities at the time and location of biopsy on a 11-point numerical rating scale (NRS).
To compare the effectiveness of supervised physical therapy program versus non-supervised on pain, functionality, fear of movement and quality of life in patients with non-specific chronic low back pain.
To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice.
Chronic pelvic pain syndrome (CPPS), is a multi-symptom syndrome with unknown etiology. The experimental autoimmune prostatitis (EAP) mouse model of CPPS is associated with immune cell infiltration into the prostate, expression of C-C Chemokine ligand 2 (CCL2) and neuroinflammation in the spinal cord. Here, we studied CCL2 expression in tissues along the nociceptive pathway and its association with neuroimmune cells during pain development. Examination of prostate tissues at days 14 and 28 after EAP induction revealed CCL2 expression was increased in epithelial cells and was associated with increased numbers of macrophages lying in close apposition to PGP9.5-positive afferent neuronal fibers. CCL2 immunoreactivity was elevated to a similar degree in the DRG at day 14 and day 28. D14 of EAP was associated with elevated IBA1 cells in the DRG that were not evident at D28. Adoptive transfer of GFP+ leukocytes into EAP mice demonstrated monocytes are capable of infiltrating the spinal cord from peripheral blood with what appeared to be a proinflammatory phenotype. In the lower dorsal spinal cord, CCL2 expression localized to NeuN expressing neurons and GFAP-expressing astrocytes. Myeloid derived cell infiltration into the spinal cord in EAP was observed in the L6-S2 dorsal horn. Myeloid derived CD45+ IBA1+ cells were localized with IBA1+ TMEM199+ microglia in the dorsal horn of the spinal cord in EAP, with intimate association of the two cell types suggesting cell-cell interactions. Lastly, intrathecal administration of liposomal clodronate ameliorated pelvic pain symptoms, suggesting a mechanistic role for macrophages and microglia in chronic pelvic pain.
The voltage-gated calcium channels CaV3.1-3.3 constitute the T-type subfamily, whose dysfunctions are associated with epilepsy, psychiatric disorders, and chronic pain. The unique properties of low voltage-activation, faster inactivation, and slower deactivation of these channels support their role in modulation of cellular excitability and low-threshold firing. Thus, selective T-type calcium channel antagonists are highly sought after. Here, we explored Ugi-azide multicomponent reaction (MCR) products to identify compounds targeting T-type calcium channel. Of the 46 compounds tested, an analog of benzimidazolonepiperidine – 5bk (1-{1-[(R)-{1-[(1S)-1-phenylethyl]-1H-1,2,3,4-tetrazol-5-yl}(thiophen-3-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one) modulated depolarization-induced calcium influx in rat sensory neurons. Modulation of T-type calcium channels by 5bk was further confirmed in whole-cell patch clamp assays in dorsal root ganglion (DRG) neurons, where pharmacological isolation of T-type currents led to a time- and concentration-dependent regulation with a low micromolar IC50. Lack of an acute effect of 5bk argues against a direct action on of T-type channels. Genetic knockdown revealed CaV3.2 to be the isoform preferentially modulated by 5bk. High voltage-gated calcium, as well as tetrodotoxin-sensitive and -resistant sodium, channels were unaffected by 5bk. 5bk inhibited spontaneous excitatory post synaptic currents and depolarization-evoked release of calcitonin gene-related peptide (CGRP) from lumbar spinal cord slices. Notably, 5bk did not bind human mu, delta, or kappa opioid receptors. 5bk reversed mechanical allodynia in rat models of HIV-associated neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), and spinal nerve ligation (SNL)-induced neuropathy, without effects on locomotion or anxiety. Thus, 5bk represents a novel T-type modulator that could be used to develop non-addictive pain therapeutics.