Role In Pain Development Research Articles

Role of Cav2.3 (R-type) Calcium Channel in Pain and Analgesia: A Scoping Review.

Voltage-gated calcium channels (VGCCs) play an important role in pain development and maintenance. As Cav2.2 and Cav3.2 channels have been identified as potential drug targets for analgesics, the participation of Cav2.3 (that gives rise to R-type calcium currents) in pain and analgesia remains incompletely understood. Identify the participation of Cav2.3 in pain and analgesia. To map research in this area as well as to identify any existing gaps in knowledge on the potential role of Cav2.3 in pain signalling, we conducted this scoping review. We searched PubMed and SCOPUS databases, and 40 articles were included in this study. Besides, we organized the studies into 5 types of categories within the broader context of the role of Cav2.3 in pain and analgesia. Some studies revealed the expression of Cav2.3 in pain pathways, especially in nociceptive neurons at the sensory ganglia. Other studies demonstrated that Cav2.3-mediated currents could be inhibited by analgesic/antinociceptive drugs either indirectly or directly. Some articles indicated that Cav2.3 modulates nociceptive transmission, especially at the pre-synaptic level at spinal sites. There are studies using different rodent pain models and approaches to reduce Cav2.3 activity or expression and mostly demonstrated a pro-nociceptive role of Cav2.3, despite some contradictory findings and deficiencies in the description of study design quality. There are three studies that reported the association of single-nucleotide polymorphisms in the Cav2.3 gene (CACNA1E) with postoperative pain and opioid consumption as well as with the prevalence of migraine in patients. Cav2.3 is a target for some analgesic drugs and has a pro-nociceptive role in pain.

Chronic pain is specifically associated with updating working memory: a longitudinal twin study.

Worse executive function (EF) is associated with chronic pain and could mechanistically contribute to pain chronification. It is unclear whether there is overall impairment in EFs or whether there are impairments in specific cognitive domains. Furthermore, the possible genetic risk underlying these associations has not been tested. Participants were from the Colorado Longitudinal Twin study; 786 same-sex twins completed a battery of EF tasks at ages 23 and/or 28 and 634 of these twins self-reported chronic pain at mean age = 28.1; prevalence = 27.76% using the Brief Pain History Questionnaire. The EF tasks were used to define a Common EF factor and 2 factors specific to updating working memory and shifting mental set. We estimated the phenotypic and genetic associations of stable EF variance across ages 23 and 28, as well as EF variance unique to age 28, with pain. With respect to stable EF variance, pain phenotypically correlated with the Updating-specific factor (r = -0.21, P = 0.008) but did not significantly correlate with the Common EF factor (r = -0.06, P = 0.350) nor with the Shifting-specific factor (r = -0.03, P = 0.709). There were no significant phenotypic correlations between pain and EF variance unique to age 28. A twin model indicated that pain and Updating-specific variance share genetic risk (rA = -0.46, P = 0.005) but not environmental risk (rE = 0.05, P = 0.844). Updating working memory shares a phenotypic and genetic relationship with pain in young adults. Impairments in gating or monitoring pain signals may play a mechanistic role in pain development.

Role of Brain Derived Neurotrophic Factor and Related Therapeutic Strategies in Central Post-Stroke Pain.

Brain-derived neurotrophic factor (BDNF) is vital for synaptic plasticity, cell persistence, and neuronal development in peripheral and central nervous systems (CNS). Numerous intracellular signalling pathways involving BDNF are well recognized to affect neurogenesis, synaptic function, cell viability, and cognitive function, which in turn affects pathological and physiological aspects of neurons. Stroke has a significant psycho-socioeconomic impact globally. Central post-stroke pain (CPSP), also known as a type of chronic neuropathic pain, is caused by injury to the CNS following a stroke, specifically damage to the somatosensory system. BDNF regulates a broad range of functions directly or via its biologically active isoforms, regulating multiple signalling pathways through interactions with different types of receptors. BDNF has been shown to play a major role in facilitating neuroplasticity during post-stroke recovery and a pro-nociceptive role in pain development in the nervous system. BDNF-tyrosine kinase receptors B (TrkB) pathway promotes neurite outgrowth, neurogenesis, and the prevention of apoptosis, which helps in stroke recovery. Meanwhile, BDNF overexpression plays a role in CPSP via the activation of purinergic receptors P2X4R and P2X7R. The neuronal hyperexcitability that causes CPSP is linked with BDNF-TrkB interactions, changes in ion channels and inflammatory reactions. This review provides an overview of BDNF synthesis, interactions with certain receptors, and potential functions in regulating signalling pathways associated with stroke and CPSP. The pathophysiological mechanisms underlying CPSP, the role of BDNF in CPSP, and the challenges and current treatment strategies targeting BDNF are also discussed.

Mode of action of astrocytes in pain: From the spinal cord to the brain.

Chronic pain is a maladaptive condition affecting 7%-10% of the population worldwide and can be accompanied by depression, anxiety, and insomnia. In particular, chronic pain is becoming more common due to the increasing incidence of diabetes mellitus, cancer, systemic (body-wide) autoimmune, trauma, and infections that attack nerve tissues with an aging global population. Upon stimuli, pain responses are evoked from nociceptive primary sensory neurons in the peripheral nervous system (PNS). Still, pathological changes leading to central sensitization of the pain circuitry in the central nervous system (CNS) is a key mechanism underlying pain maintenance. In humans, chronic pain can last for years, even after the observable signs and symptoms of the primary inflammation or damage have resolved. It is clear that astrocytes, the most abundant cell type in the CNS, are highly involved in regulating pain signaling under health and disease. Multiple astrocyte subsets and diversified activation states driven by intrinsic and extrinsic cues have recently been identified in the spinal cord and brain, playing complex roles in pain development and resolution. Targeting detrimental astrocyte subtypes and activity is considered a promising pain management strategy. Here, we integrate the latest findings to review differential astrocytes activities in distinct regions of the CNS during pain pathophysiology and discuss the underlying molecular mechanisms that control their mode of action in beneficial or/and harmful aspects of pain. Finally, we provide a translational overview of current progress for pain therapies via modulating astrocytic activity.

Sympathectomy Ameliorates CFA-Induced Mechanical Allodynia via Modulating Phenotype of Macrophages in Sensory Ganglion in Mice.

The sympathetic nervous system (SNS) is suggested to be involved in some forms of pain, but the mechanisms of which are incompletely known. Moreover, there is a lack of information on the regulatory role of the SNS on macrophages in sensory ganglion, which plays an important role in pain development. The present study aims to investigate the effects of the SNS on orofacial inflammatory pain and examine, if any, how the SNS influences trigeminal ganglion (TG) macrophage responses. Sympathectomy was performed on male C57BL/6 mice before receiving a local injection of Complete Freund's adjuvant (CFA) to induce inflammatory pain. Effects of sympathectomy on orofacial pain were examined by Von Frey test and c-Fos expression. Polarization of TG macrophage was evaluated by immunohistochemistry and the level of norepinephrine (NE) in the TG were determined by liquid chromatography. Sympathetic signaling to TG macrophages were predicted based on single-cell analysis. CFA injection induced a significant increase in mechanical allodynia, the number of c-Fos-positive neuron, and the level of NE in TG, which were largely reduced by sympathectomy. The number of M1 macrophages was markedly increased by CFA and was largely reduced by sympathectomy from 1 to 14 days post-injection. Single-cell RNA sequencing analysis and immunofluorescence staining showed that TG macrophages mainly express β2 adrenergic receptors for NE. Cell-cell communication analysis predicted sympathetic signaling that may modulate macrophage phenotypes, including Colony-stimulating factor-1, Migration inhibitory factor, Pleiotrophin and Nicotinamide phosphoribosyl transferase. The SNS may involve in CFA-induced mechanical allodynia via modulating macrophage phenotypes in the TG. Targeting sympathetic activation might be useful in treating some painful conditions in the orofacial region.

TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function

The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1′s actions in the homeostasis of Ca2+ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.

Pain in cervical dystonia and the antinociceptive effects of botulinum toxin: what is currently known?

Pain is the most common and disabling non-motor symptom in cervical dystonia (CD). Up to 88.9% of patients report pain at some point in the course of the disease. It is still a matter of debate whether CD-related pain originates only from prolonged muscle contraction. Recent data suggest that the alterations of transmission and processing of nociceptive stimuli play a crucial role in pain development. Botulinum toxin (BT) is the first-line therapy for CD. Despite fully elucidated muscle relaxant action, the antinociceptive effect of BT remains unclear and probably exceeds a simple decompression of the nerve fibers due to the reduction in muscle tone. The proposed mechanisms of the antinociceptive action of BT include inhibition of pain mediator release, inhibition of membrane sodium channels, retrograde axonal transport and impact on the other pain pathways. This article summarizes the current knowledge about the antinociceptive properties of BT and the clinical analgesic efficacy in the treatment of CD patients.

Exercise-Induced Changes to the Macrophage Response in the Dorsal Root Ganglia Prevent Neuropathic Pain after Spinal Cord Injury.

Spinal cord injury (SCI) induces neuropathic pain that is refractory to treatment. Central and peripheral immune responses to SCI play critical roles in pain development. Although immune responses in the dorsal horn have been implicated in SCI-pain, immune mechanisms in the periphery, especially in the dorsal root ganglia (DRG), where nociceptor cell bodies reside, have not been well studied. Exercise is an immunomodulator, and we showed previously that early exercise after SCI reduces pain development. However, the mechanisms of exercise-mediated pain reduction are not understood. Therefore, we examined the 1) underlying immune differences in the spinal cord and DRG between rats with and without pain and 2) immunomodulatory effects of exercise in pain reduction. Rats were subjected to a unilateral contusion at C5 and tested for pain development using von Frey and mechanical conflict-avoidance paradigms. A subgroup of rats was exercised on forced running wheels starting at 5 days post-injury for 4 weeks. We observed greater microglial activation in the C7-C8 dorsal horn of rats with SCI-induced pain compared to rats with normal sensation, and early exercise reduced this activation independently of pain behavior. Further, abnormal pain sensation strongly correlated with an increased number of DRG macrophages. Importantly, exercise-treated rats that maintain normal sensation also have a lower number of macrophages in the DRG. Our data suggest that macrophage presence in the DRG may be an important effector of pain development, and early wheel walking exercise may mediate pain prevention by modulating the injury-induced macrophage response in the DRG. Further supportive evidence demonstrated that rats that developed pain despite exercise intervention still displayed a significantly elevated number of macrophages in the DRG. Collectively, these data suggest that macrophage presence in the DRG may be an amenable cellular target for future therapies.

Inflammaging in the intervertebral disc

Degeneration of the intervertebral disc – triggered by ageing, mechanical stress, traumatic injury, infection, inflammation and other factors – has a significant role in the development of low back pain. Back pain not only has a high prevalence, but also a major socio-economic impact. With the ageing population, its occurrence and costs are expected to grow even more in the future. Disc degeneration is characterized by matrix breakdown, loss in proteoglycans and thus water content, disc height loss and an increase in inflammatory molecules. The accumulation of cytokines, such as interleukin (IL)-1β, IL-8 or tumor necrosis factor (TNF)-α, together with age-related immune deficiency, leads to the so-called inflammaging – low-grade, chronic inflammation with a crucial role in pain development. Despite the relevance of these molecular processes, current therapies target symptoms, but not underlying causes. This review describes the biological and biomechanical changes that occur in a degenerated disc, discuss...

Elevated Nerve Growth Factor/p75NTR Co-localization In Smokers After Eccentric Exercise

PURPOSE: Smoking increases musculoskeletal injury risk and protracts healing. While the underlying mechanisms are poorly understood, altered inflammatory responses may contribute. We previously found at 48h post-eccentric contractions (ECC) that smokers (SM) experienced: 1) 15% greater delayed onset muscle soreness (DOMS) than non-smokers (NS); and 2) altered muscle activity of key pro-inflammatory regulator canonical nuclear factor kappa-beta (p65 NFκB; NS: -7.1±1.3 fold change from baseline; SM: -1.1±1.0 fold). Coinciding with a shift from pro- to anti-inflammatory signaling and peak DOMS, these data suggest delayed inflammatory resolution in SM. Nerve growth factor (NGF) plays a role in pain development and is stimulated by p65 NFκB. We hypothesized that NGF expression and co-localization with both high- (tyrosine receptor kinase A, TrkA) and low- (p75NTR) affinity receptors would be greater in SM than NS following ECC, and may explain greater DOMS in SM. METHODS: Young adult male SM (N=6) and NS (N=5) performed 100 maximal ECC using only the non-dominant knee extensors. Bilateral vastus lateralis biopsies were obtained at 48h post-exercise for NGF mRNA quantification via qPCR. Immunohistochemistry was performed on a subcohort (n=3/group) to quantify and localize NGF, TrkA, and p75NTR protein. RESULTS: ECC did not alter NGF mRNA (NS: 1.9±0.3 fold; SM: 2.8±0.7 fold; p=0.09) or protein levels, which were similarly induced in SM compared to NS (1.1 fold). NGF co-localization with TrkA was unrelated to exercise or smoking status (~23.2±2%). However, SM expressed 2.1 fold higher p75NTR levels than NS (p<0.05). Further, there was a significant interaction (p<0.05) whereby NGF/p75NTR co-localization after ECC decreased in NS (control: 39.6±8.1%; exercise: 31.3±11.4%) but increased in SM (control: 59.2±8.4%; exercise: 72.4±13.7%). CONCLUSIONS: Greater p75NTR expression and p75NTR/NGF co-localization may enhance nerve sensitivity in SM and further augment DOMS. Along with our previous DOMS and inflammatory findings, p75NTR/NGF in SM could delay inflammatory resolution, enhancing risk for chronic pain/disability. This work provides insights into mechanisms that may place SM at greater risk for musculoskeletal injury and impaired healing. Supported, in part, by a grant from the Department of Defense.

Kinesin superfamily protein 17 contributes to the development of bone cancer pain by participating in NR2B transport in the spinal cord of mice

Τreatment of bone cancer pain remains a challenge, while the mechanisms causing the pain remain elusive. We demonstrated that the expression of the N‑methyl‑D‑aspartate (NMDA) receptor NR2B subunit was upregulated in mice with bone cancer pain. Kinesin superfamily protein 17 (KIF17), a recently characterized member of the kinesin superfamily proteins, has been demonstrated to transport and deliver the NR2B subunit to dendrites in mammalian neurons. In the present study, we induced bone cancer pain via femur bone cavity osteosarcoma NCTC 2472 tumor cell implantation (TCI) in mice. The results showed that TCI in mice increased the number of spontaneous flinches, mechanical allodynia events, expression of spinal KIF17 and NR2B subunits. Intrathecal administration of KIF17 antisense oligodeoxynucleotide (ODN) attenuated the behavioral signs of bone cancer pain and suppressed the increased expression of NR2B induced by TCI. In addition, KIF17 binds to a protein complex that contains mLin‑10 to transport NR2B, and we determined that the increase of mLin‑10 was suppressed following admini-stration. Thus, these findings suggested that KIF17 contributed to the development of bone cancer pain in the spinal cord through NR2B transport and that mLin‑10 may also play a role in pain development.

Inflammatory Mediators in Intervertebral Disk Degeneration and Discogenic Pain

Although degeneration of the intervertebral disk has historically been described as a misbalance between anabolic and catabolic factors, the role of inflammatory mediators has long been neglected. However, past research clearly indicates that inflammatory mediators such as interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor-α are expressed at higher levels in “diseased” intervertebral disks. Both disk cells as well as invading macrophages can be the source of the detected cytokines. Importantly, occurrence of inflammatory mediators in the disk can worsen the progress of degeneration by inducing the expression of matrix degrading enzymes as well as by inhibiting extracellular matrix synthesis. In addition, inflammatory mediators play a crucial role in pain development during intervertebral disk herniation (i.e., sciatica) and disk degeneration (i.e., discogenic pain). This review provides information on the most relevant inflammatory mediators during different types of disk diseases and explains how these factors can induce disk degeneration and the development of discogenic and sciatic/radiculopathic pain.

Exercise Training for Peripheral Arterial Disease

Exercise Training for Peripheral Arterial Disease