YokoCo

Prolonged experimental pain can help assess cortical mechanisms underlying the transition from acute to chronic pain such as resting-state functional connectivity (rsFC), especially in early stages. This crossover study determined the effects of 24-hour-capsaicin-induced pain on the default mode network rsFC, a major network in the dynamic pain connectome. Electroencephalographic rsFC measured by Granger causality was acquired from 24 healthy volunteers (12 women) at baseline, 1hour, and 24hours following a control or capsaicin patch on the right forearm. The control patch was received maximum one week before the capsaicin patch. Following 24hours, the patch was cooled and later heated to assess rsFC changes in response to pain relief and facilitation, respectively. Compared to baseline, decreased rsFC at alpha oscillations (8-10Hz) was found following 1hour and 24hours of capsaicin application for connections projecting from medial prefrontal cortex (mPFC) and right angular gyrus (rAG) but not left angular gyrus (lAG) or posterior cingulate cortex (PCC): mPFC-PCC (1hour:P<0.001, 24hours_P=0.002), mPFC-rAG (1hour:P<0.001, 24hours_P=0.001), rAG-mPFC (1hour:P<0.001, 24hours_P=0.001), rAG-PCC (1hour:P<0.001, 24hours_P=0.004). Comparable decreased rsFC following 1hour and 24hours (P≤0.008) was found at beta oscillations, however, decreased projections from PCC were also found: PCC-rAG (P≤0.005) and PCC-lAG (P≤0.006). Pain NRS scores following 24hours (3.7±0.4) was reduced by cooling (0.3±0.1, P=0.004) and increased by heating (4.8±0.6, P=0.016). However, neither cooling nor heating altered rsFC. This study shows that 24hours of experimental pain induces a robust decrease in DMN connectivity that persists during pain relief or facilitation suggesting a possible shift to attentional and emotional processing in persistent pain. Perspective: This article shows decreased DMN connectivity that might reflect possible attentional and emotional changes during acute and prolonged pain. Understanding these changes could potentially help clinicians in developing therapeutic methods that can better target these attentional and emotional processes before developing into more persistent states.

Previous studies have reported that L5/L6 spinal nerve ligation (SNL), but not L5 spinal nerve transection (SNT), enhances anoctamin-1 in injured and uninjured dorsal root ganglia (DRG) of rats suggesting some differences in function of the type of nerve injury. The role of bestrophin-1 in these conditions is unknown. The aim of this study was to investigate the role of bestrophin-1 in rats subjected to L5 spinal nerve transection (SNT) and L5/L6 spinal nerve ligation (SNL). SNT up-regulated bestrophin-1 protein expression in injured L5 and uninjured L4 DRG at day 7, whereas it enhanced GAP43 mainly in injured, but also in uninjured DRG. In contrast, SNL enhanced GAP43 at day 1 and 7, while bestrophin-1 expression increased only at day 1 after nerve injury. Accordingly, intrathecal injection of the bestrophin-1 blocker CaCC (1-10 µg) reverted SNT- or SNL-induced tactile allodynia in a concentration-dependent manner. Intrathecal injection of CaCC (10 µg) prevented SNT-induced upregulation of bestrophin-1 and GAP43 at day 7. In contrast, CaCC did not affect SNL-induced up-regulation of GAP43 nor bestrophin-1. Bestrophin-1 was mainly expressed in small- and medium-size neurons in naïve rats, while SNT increased bestrophin-1 immunoreactivity in CGRP+, but not in IB4+ neuronal cells in DRG. Intrathecal injection of bestrophin-1 plasmid (pCMVBest) induced tactile allodynia and increased bestrophin-1 expression in DRG and spinal cord in naïve rats. CaCC reversed bestrophin-1 overexpression-induced tactile allodynia and restored bestrophin-1 expression. Our data suggest that bestrophin-1 plays a relevant role in neuropathic pain induced by SNT, but not by SNL. Perspective: SNT, but not SNL, up-regulates bestrophin-1 and GAP43 protein expression in injured L5 and uninjured L4 DRG. Moreover, SNT increases bestrophin-1 immunoreactivity in CGRP+ neurons in DRG, while bestrophin-1 overexpression induces allodynia. CaCC reduces allodynia and restores bestrophin-1 expression induced by bestrophin-1 transfection. Our data suggest that spinal bestrophin-1 in DRG is differentially regulated depending on the neuropathic pain model.

Our understanding of neuropathic itch is limited, due to the lack of relevant animal models. Patients with cutaneous T-cell lymphoma (CTCL) suffer from severe itching. Here we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produces time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early-phase (20 days), CTCL causes hyper-innervations in the epidermis. However, chronic itch is associated with loss of epidermal nerve fibers in the late-phases (40 and 60 days). CTCL is also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early- and late-phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal gabapentin injection reduced late-phase but not early-phase pruritus. IL-31 is upregulated in mouse lymphoma, while its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in CTCL mice. Intratumoral anti-IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, intrathecal administration of TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

Previous functional magnetic resonance imaging studies have substantiated changes in multiple brain regions of functional activity in patients with vestibular migraine. However, few studies have assessed functional connectivity within and between specific brain networks in vestibular migraine.

Diseases of joints are among the most frequent causes of chronic pain. In the course of joint diseases the peripheral and the central nociceptive system develop persistent hyperexcitability (peripheral and central sensitization). This review addresses the mechanisms of spinal sensitization evoked by arthritis. Electrophysiological recordings in anaesthetized rats from spinal cord neurons with knee input in a model of acute arthritis showed that acute spinal sensitization is dependent on spinal glutamate receptors (AMPA, NMDA and metabotropic glutamate receptors) and supported by spinal actions of neuropeptides such as neurokinins and CGRP, by prostaglandins, and by proinflammatory cytokines. In several chronic arthritis models (including immune-mediated arthritis and osteoarthritis) spinal glia activation was observed to be coincident with behavioral mechanical hyperalgesia which was attenuated or prevented by intrathecal application of minocycline, fluorocitrate and pentoxyfylline. Some studies identified specific pathways of micro- and astroglia activation such as the purinoceptor- (P X -) cathepsin S/CX CR1 pathway, the mobility group box-1 protein (HMGB1) and toll-like receptor 4 (TLR4) activation, spinal NFκB/p65 activation and others. The spinal cytokines TNF, interleukin-6, interleukin-1β and others form a functional spinal network characterized by an interaction between neurons and glia cells which is required for spinal sensitization. Neutralization of spinal cytokines by intrathecal interventions attenuates mechanical hyperalgesia. This effect may in part result from local suppression of spinal sensitization and in part from efferent effects which attenuate the inflammatory process in the joint. In summary, arthritis evokes significant spinal hyperexcitability which is likely to contribute to the phenotype of arthritis pain in patients.

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel-mediated neural circuit basis for RIH that can guide analgesic development.

Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.

Previous literature suggests that kidney transplant recipients (KTRs) do not use the majority of opioid tablets prescribed after transplant surgery. This study analyzed the effectiveness of a new pain management guidance in KTRs after discharge from transplant surgery at a renal transplant center. The single center pre-, post- study compared the number of opioid refill requests, patient-reported pain control, multimodal analgesic agents, and opioid tablets prescribed at discharge in both pre- and post- cohorts. A total of 127 patients were included. Data was collected through standardized patient interviews and chart review from electronic medical records. The pre-guidance and post-guidance cohorts had no detectable difference in refill requests (p = 0.365) nor pain control (p = 0.324) post-discharge. The post-group had a significant reduction in opioid tablets prescribed at discharge (22 tablets ± 10 vs 10 tablets ± 2, p = <0.0001) with a significant increase in acetaminophen (p = 0.005) and lidocaine patches (p = <0.0001) prescribed at discharge. Both groups used a mean of three opioid tablets within the first week after discharge. The guidance resulted in 700 fewer opioid tablets in the community during the study time frame, with no difference in pain control nor refill requests after discharge.

This systematic review describes herpes zoster (HZ) economic burden in terms of healthcare resource use and cost outcomes in the Latin America and Caribbean (LAC) region. We searched online databases from 1 January 2000 to 20 February 2020 to identify eligible publications. We identified 23 publications that reported direct costs, indirect costs, and resources associated with HZ and its complications. The primary direct medical resources reported in the different studies were visits to doctors, transportation, days in the hospital, nursing, medication schedules, and physical therapy. Direct total costs per patient ranged from $99.99 to $4177.91. The highest cost was found in Brazil. Direct costs are, in average, 81.39% higher than indirect costs. The cost per patient that includes postherpetic neuralgia treatment is 115% higher on average for the directs and 73% for the indirect costs. Brazil reported a higher total cost per patient than Argentina and Mexico, while for indirect costs per patient, Brazil and Argentina had higher costs than Mexico, respectively. A meta-analysis on the number of days due to HZ hospitalization, performed on non-immunosuppressed patients over 65 years of age from three studies, resulted in a cumulative measure of 4.5 days of hospitalization. In the LAC region, the economic burden of HZ and associated complications is high, particularly among high-risk populations and older age groups. Preventative strategies such as vaccination could help avoid or reduce the HZ-associated disease economic burden in the LAC region.

Anterior cruciate ligament reconstruction (ACLR) results in persistent altered knee biomechanics, but contributing factors such as pain or patient function, leading to the altered loading, are unknown.