HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

2016 ◽  
Vol 473 (18) ◽  
pp. 2717-2736 ◽  
Author(s):  
Christoforos Tsantoulas ◽  
Elizabeth R. Mooney ◽  
Peter A. McNaughton
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Ion Channels ◽  
Warning Signal ◽  
Sensory Nerves ◽  
Nociceptive Neurons ◽  
Pain Syndromes ◽  
Medical Need ◽  
Pathological Pain ◽  
Genetic Deletion

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

scholarly journals VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

2021 ◽  
Author(s):  
Laura Micheli ◽  
Carmen Parisio ◽  
Elena Lucarini ◽  
Alessia Vona ◽  
Alessandra Toti ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Treatment ◽  
Electrophysiological Study ◽  
Chemotherapeutic Agents ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Nociceptive Neurons ◽  
Medical Need ◽  
Pathological Pain ◽  
Endothelial Growth Factor

AbstractChemotherapy-induced neuropathic pain is a clinically relevant adverse effect of several anticancer drugs leading to dose reduction or therapy discontinuation. The lack of knowledge about the mechanisms of neuropathy development and pain chronicization makes chemotherapy-induced neuropathic pain treatment an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a neurotoxicity biomarker in a model of chemotherapy-induced neuropathy, and its decrease has been related to pain relief. Aim of this study was to clarify the VEGF-A-dependent pain signaling in the CNS for individuating new targeted therapeutic approaches. In mice, the intrathecal infusion of VEGF-A induced a dose-dependent noxious hypersensitivity mediated by the VEGF receptor 1 (VEGFR-1) as demonstrated by pharmacological and genetic tools. In electrophysiological study, VEGF-A stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord, VEGF-A increased in astrocytes of animals affected by neuropathy suggesting this cell population as a source of the potent pain mediator. Accordingly, the selective knockdown of astrocytic VEGF-A, by shRNAmir, blocked the development of oxaliplatin-induced neuropathic pain. Besides, the anti-VEGFR-1 mAb D16F7 (previously described as anticancer) effectively relieved neuropathic pain induced by chemotherapeutic agents. In conclusion, astrocyte-released VEGF-A is a new player in the complex neuron-glia network that oversees physiological and pathological pain and D16F7 mAb rises as a potent pain killer strategy.

scholarly journals Sickle cell pain: a critical reappraisal

Blood ◽  
2012 ◽  
Vol 120 (18) ◽  
pp. 3647-3656 ◽  
Author(s):  
Samir K. Ballas ◽  
Kalpna Gupta ◽  
Patricia Adams-Graves
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Sickle Cell ◽  
Multiorgan Failure ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Prodromal Phase ◽  
Pain Syndromes ◽  
Painful Episode ◽  
Chronic Pain Syndromes

AbstractSickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes.

scholarly journals 2255

2017 ◽  
Vol 1 (S1) ◽  
pp. 26-26
Author(s):  
Shona Ray-Griffith ◽  
Bethany Morrison ◽  
Pedro Delgado ◽  
Everett Magann ◽  
Michael Mancino ◽  
...  
Keyword(s):  
Mental Health ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Pregnant Women ◽  
Health Program ◽  
Chart Review ◽  
Mental Health Program ◽  
Medication History ◽  
Pain Syndromes ◽  
Chronic Pain Syndromes

OBJECTIVES/SPECIFIC AIMS: (1) Characterize the prevalence and initial pharmacological management of chronic pain syndromes during pregnancy in a women’s mental health program. (2) Describe the severity and qualitative characteristics of chronic pain during pregnancy and the acute postpartum period. (3) Compare obstetrical and neonatal outcomes between pregnant women with and without chronic pain syndromes. METHODS/STUDY POPULATION: A chart review was conducted to identify all pregnant women who presented for an initial evaluation to the Women’s Mental Health Program (WMHP) at the University of Arkansas for Medical Sciences from July 2013 to June 2016. We excluded respondents <18 years of age or who did not consent to having their information used for research purposes. Demographic information, past and current medical histories, and medication history were obtained from written and electronic medical records. Chronic pain complaints and medication history are presented as counts and percentages. In an ongoing prospective, longitudinal study of pregnant women with chronic pain, women are enrolled before 20 weeks gestation and followed throughout pregnancy and the first 3 months postpartum. Study visits occur at 4-week intervals; and pain characteristics, analgesic exposures, other medications, and depressive measures are collected. Obstetrical and neonatal outcomes are obtained following delivery. Subjects will be compared based on pain types (ie, neuropathic pain, non-neuropathic pain, and controls) and treatment exposures (eg, +/− opioids). Primary outcome measures include visual analog scale (VAS). Secondary outcome measures include other pain and depression assessments. Data will be analyzed using SAS 9.4. A p-value of<0.05 was considered statistically significant. RESULTS/ANTICIPATED RESULTS: (1) Chronic pain conditions were reported by 28.2% (44/156) of the initial referrals to the WMHP. (2) 95.5% of respondents with chronic pain were taking at least 1 medication, and 59.5% were taking 2 or more medications. Mean number of medications used were 2.6±2.1.3. The most common medications reported were acetaminophen (43.2%), opioids (43.2%), and sedative/hypnotics (36.4%). Non-pharmacological therapy (eg, physical therapy and transcutaneous electrical nerve stimulation) was reported by 20.5% of respondents. (4) We anticipate that measures of pain severity will increase in pregnancy, peak in the third trimester, and decline in the postpartum period. (5) We foresee that the prospective results will confirm the chart review as indicated by a higher rate of medication exposures during pregnancy, including non-analgesic medications in the women with chronic pain syndromes. (6) We expect women with chronic pain syndromes to have a higher rate of obstetrical complications, specifically pre-term delivery and operative delivery. (7) Finally, we anticipate that chronic pain syndromes and management will result in a higher rate of neonatal complications, specifically neonatal intensive care unit admission, neonatal respiratory problems, and small for gestational age infants. DISCUSSION/SIGNIFICANCE OF IMPACT: Chronic pain syndromes are prevalent in more than one-quarter of pregnant women in our study with the majority of women using pharmacological agents to manage their condition. This prevalence is greater or equal to than other common obstetrical conditions, such as gestational diabetes or preterm delivery. The novel prospective data will be germane to the clinical care of pregnant women with chronic pain disorders. Clinical practice will be better informed by our data regarding the potential impact of chronic pain and its management on pregnancy course and perinatal outcomes. These data will provide the initial foundation for the development of treatment guidelines for the management of chronic pain syndromes during the perinatal period.

Sympathetic component of neuropathic pain: Animal models and clinical diagnosis

1997 ◽  
Vol 20 (3) ◽  
pp. 468-469
Author(s):  
Laszlo A. Urban
Keyword(s):  
Experimental Data ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Clinical Diagnosis ◽  
Inflammatory Pain ◽  
Ongoing Debate ◽  
Pain Syndromes ◽  
Sympathetic Nervous

Although clinical studies and animal models seem to establish an important role for the sympathetic nervous system in many forms of neuropathic and inflammatory pain, there is an ongoing debate on the classification of pain syndromes with sympathetic components. The confusion originates from several sources: failure to acknowledge that the pathomechanism of chronic pain can change during the progress of the disease, which is now strongly underlined by experimental data from suitable animal models. Neuropathic pain is a vaguely defined collection of pain syndromes which includes painful conditions with diverse and largely unknown patho-mechanisms. Clinical diagnosis is difficult and well designed, placebo controlled sympathectomy is rarely performed. [blumberg et al.]

scholarly journals Spinal NGF Restores Opioid Sensitivity in Neuropathic Rats: Possible Role of NGF as a Regulator of CCK-Induced Anti-Opioid Effects

2000 ◽  
Vol 5 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Catherine M Cahill ◽  
Terence J Coderre
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Postnatal Period ◽  
Spontaneous Pain ◽  
Pain Mechanisms ◽  
Nociceptive Neurons ◽  
Nociceptive Transmission ◽  
Chronic Pain Conditions ◽  
Injury Models

The breadth of peripheral effects produced by nerve growth factor (NGF) in nociceptive processing has been well documented. However, less is known about the functional significance of central NGF in nociceptive transmission. The effect of NGF on the nervous system is dependent on the developmental stage. During the prenatal developmental period, NGF is critical for survival of nociceptors; in the postnatal period it regulates the expression of nociceptor phenotype, and in the adult it contributes to pain following an inflammatory insult. The implications for central NGF in the expression and regulation of spinal neuropeptides that are involved in pain mechanisms are reviewed. Knowledge has been gained by studies using peripheral nerve injury models that cause a deprivation of central NGF. These models also give rise to the development of pain syndromes, which encompass spontaneous pain, hyperalgesia and allodynia, routinely referred to as neuropathic pain. These models provide an approach for examining the contribution of central NGF to nociceptive transmission. Chronic pain emanating from a nerve injury is typically refractory to traditional analgesics such as opioids. Recent evidence suggests that supplementation of spinal NGF restores morphine-induced antinociception in an animal model of neuropathic pain. This effect appears to be mediated by alterations in spinal levels of cholecystokinin. The authors hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.

scholarly journals Neuropathic pain

2021 ◽  
pp. 58-64
Author(s):  
V. A. Koriachkin ◽  
A. P. Spasova ◽  
V. V. Khinovker
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Correct Diagnosis ◽  
Epidemiological Studies ◽  
Chronic Neuropathic Pain ◽  
Official Document ◽  
Adequate Treatment ◽  
Pain Syndromes ◽  
Recent Classification

Background Chronic neuropathic pain is a common occurrence, its prevalence ranges from 7 to 10% of the total population. Currently, the only official document that includes neuropathic pain is the International Classification of Headaches Disorders (ICHD-3), in which this type of pain is associated with traumatic brain injury and neuralgia. Until now, there has been no generally accepted terminology and classification of chronic neuropathic pain.Objective To provide the current terminology, classification and additional characteristics of neuropathic chronic pain.Results The review of modern terminology and classification of neuropathic chronic pain describes the terms included in the concept of chronic peripheral and central neuropathic pain, identifies pain subtypes, as well as its additional characteristics such as the intensity of neuropathic pain, the severity of suffering and disability.Conclusions Thus, the presented recent classification of chronic neuropathic pain is an exhaustive list of the most common neuropathic pain syndromes. The inclusion of classification into clinical practice will help to draw attention to the problem of treatment of chronic neuropathic pain by WHO members, carrying out epidemiological studies and making a correct diagnosis, and therefore the appointment of adequate treatment methods.

Opioids as a Treatment Option for MS Patients with Chronic Pain

2005 ◽  
Vol 7 (1) ◽  
pp. 10-15 ◽  
Author(s):  
Anthony H. Guarino ◽  
Martha Cornell
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Treatment Option ◽  
Opioid Therapy ◽  
Term Therapy ◽  
Drug Category ◽  
Pain Syndromes ◽  
Long Term Therapy ◽  
Addictive Potential

Neuropathic and nociceptive pain are commonly observed in patients with MS. Among the analgesic options available for treating pain in MS, opioids may be too often avoided because of concerns about prescribing restrictions and addictive potential. However, when these fears are misplaced, they deny the patient of a powerful and potentially effective pain reduction option. Proper screening and management can help select appropriate patients for opioid therapy and maintain patients on long-term therapy while monitoring for signs of behaviors such as addiction or diversion. One such method involves entering into a “contract” with the patient with guidelines for renewing prescriptions. Although the literature contains few studies on opioids specific to MS patients, a number of studies support the use of this drug category in patients experiencing neuropathic pain syndromes.

scholarly journals SPINAL CORD STIMULATION IN TREATMENT OF THE NEUROPATHIC PAIN SYNDROMES: INITIAL EXPERIENCE

2010 ◽  
Vol 16 (2) ◽  
pp. 68-71
Author(s):  
D. A. Rzaev ◽  
V. V. Rudenko ◽  
I. L. Pudovkin ◽  
A. P. Tatarintsev ◽  
D. S. Godanyuk
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Spinal Cord Stimulation ◽  
Pulse Generator ◽  
Initial Experience ◽  
Pain Syndromes ◽  
Chronic Pain Syndromes

In the article initial experience of spinal cord stimulation for chronic pain syndromes is described. The trial was done for 62 patients, in 52 cases trial was successful and subcutaneous pulse generator were implanated. Maximal follow-up is 26 months. The level of pain evaluates at VAS. Permanent pain-relieve results were achieved in 46 patients (74,2%). These results correspond to literature data.

Pain Syndromes Other Than Headache

2016 ◽  
Author(s):  
Edgar L. Ross
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Sensory Processing ◽  
Pain Syndrome ◽  
The Body ◽  
Spinal Cord Dorsal Horn ◽  
Opioid Use ◽  
Nerve Injuries ◽  
Pain Syndromes ◽  
Chronic Pain Syndromes

Pain is experienced within a complex biologic, emotional, psychological, and social context that may defy physical examination, diagnostic procedures, and laboratory tests. This chapter aims to empower internists to improve their medical practices in pain management. It provides a scientific background that covers nociception and how sensory processing occurs at multiple levels in the body. Clinical assessment is detailed, as well as diagnostic categories that include mixed or uncertain chronic pain syndromes (back pain, fibromyalgia, postamputation pain, pain from cancer and bone) and neuropathic pain syndromes (polyneuropathy, mononeuropathy multiplex, ganglionopathy, genetic disorders, focal and regional syndromes). Treatment of chronic pain can be surgical or interventional. Pharmacologic treatment for acute and chronic nociceptive pain includes special considerations for geriatric and terminal patients. For treatment of neuropathic pain, medications are the major component. One tables lists iatrogenic nerve injuries that can cause posttraumatic neuralgia and complex regional pain syndrome. Other tables detail stepwise pharmacologic management of neuropathic pain and cite recommendations on opioid use from the Centers for Disease Control and Prevention. One figure illustrates how pain transducers monitor and influence tissue conditions. Other figures show sensory processing in the spinal cord dorsal horn, physical findings in the feet of patients with bilateral foot pain from small-fiber polyneuropathy, illustrate how examination can identify specific nerve injuries causing chronic pain, and provide classification of chronic pain syndromes. This chapter contains 82 references.

Antidepressants in the Treatment of Chronic Pain

1998 ◽  
Vol 11 (5) ◽  
pp. 388-393 ◽  
Author(s):  
Cherry W. Jackson
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Cancer Pain ◽  
Musculoskeletal Pain ◽  
Antidepressant Activity ◽  
Controlled Trials ◽  
Analgesic Action ◽  
Pain Syndromes ◽  
Antidepressant Effects ◽  
Chronic Pain Syndromes

Antidepressants have been successfully used for chronic pain syndromes for approximately 30 years. One theory is that analgesic action is secondary to the antidepressant effects of the medications. Placebo-controlled trials have documented that antidepressants treat neuropathic pain, musculoskeletal pain, chronic pain, and cancer pain. The most frequently studied antidepressant for pain is amitriptyline. Other antidepressants that have shown analgesic activity include imipramine, citalopram, paroxetine, nortriptyline, desipramine, and mianserin. Fluoxetine and trazodone have not been shown to successfully treat pain syndromes. Venlafaxine, a new antidepressant, most recently was shown to have antidepressant activity in fibromyalgia. More studies need to be done with newer antidepressants to confirm their place in treating pain syndromes.

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