Single-Dose P2 X4R Single-Chain Fragment Variable Antibody Permanently Reverses Chronic Pain in Male Mice

Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

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Sexual dimorphism in cognitive disorders in a murine model of neuropathic pain

Behavioral and Brain Functions ◽

10.1186/s12993-019-0164-0 ◽

2020 ◽

Vol 16 (1) ◽

Cited By ~ 1

Author(s):

Soonmi Won ◽

Keebum Park ◽

Hyoungsub Lim ◽

Sung Joong Lee

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Cognitive Deficits ◽

Water Maze ◽

Cognitive Disorders ◽

Male Mice ◽

Chronic Neuropathic Pain ◽

Male And Female ◽

Novel Object ◽

Female Mice

Abstract Background A sex-difference in susceptibility to chronic pain is well-known. Although recent studies have begun to reveal the sex-dependent mechanisms of nerve injury-induced pain sensitization, sex differences in the affective and cognitive brain dysfunctions associated with chronic pain have not been investigated. Therefore, we tested whether chronic pain leads to affective and cognitive disorders in a mouse neuropathic pain model and whether those disorders are sexually dimorphic. Methods Chronic neuropathic pain was induced in male and female mice by L5 spinal nerve transection (SNT) injury. Pain sensitivity was measured with the von Frey test. Affective behaviors such as depression and anxiety were assessed by the forced swim, tail suspension, and open field tests. Cognitive brain function was assessed with the Morris water maze and the novel object location and novel object recognition tests. Results Mechanical allodynia was induced and maintained for up to 8 weeks after SNT in both male and female mice. Depressive- and anxiety-like behaviors were observed 8 weeks post-SNT injury regardless of sex. Chronic pain-induced cognitive deficits measured with the Morris water maze and novel object location test were seen only in male mice, not in female mice. Conclusions Chronic neuropathic pain is accompanied by anxiety- and depressive-like behaviors in a mouse model regardless of sex, and male mice are more vulnerable than female mice to chronic pain-associated cognitive deficits.

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Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0111 ◽

2019 ◽

Vol 20 (1) ◽

pp. 95-108

Author(s):

Adriana Miclescu ◽

Antje Straatmann ◽

Panagiota Gkatziani ◽

Stephen Butler ◽

Rolf Karlsten ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Upper Extremity ◽

Nerve Injury ◽

Persistent Pain ◽

Peripheral Nerve Injuries ◽

Nerve Injuries ◽

Chronic Neuropathic Pain ◽

Younger Age

AbstractBackground and aimsAside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed.MethodsA standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors.ResultsMore than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019).ConclusionsA high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

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INFLUENCE OF CHRONIC NEUROGENIC PAIN ON THE DYNAMICS OF THE NO-SYSTEM FUNCTIONING DURING MELANOMA B16/F10 GROWTH IN MALE MICE

Siberian Journal of Oncology ◽

10.21294/1814-4861-2021-20-3-67-75 ◽

2021 ◽

Vol 20 (3) ◽

pp. 67-75

Author(s):

O. I. Kit ◽

I. M. Kotieva ◽

E. M. Frantsiyants ◽

E. I. Surikova ◽

I. V. Kaplieva ◽

...

Keyword(s):

Gender Differences ◽

Neuropathic Pain ◽

Growth Factors ◽

Sciatic Nerve ◽

Tumor Growth ◽

Male Mice ◽

Neurogenic Pain ◽

Chronic Neuropathic Pain ◽

Tumor Tissues ◽

System Functioning

Since B16/F10 melanoma demonstrated gender differences in its growth in the presence of chronic neuropathic pain (cnp) and changes in the system of proangiogenic growth factors, the aim of the study was to analyze levels of components of the no-system in male mice during the growth of transplantable B16/F10 melanoma in the presence of cnp.Material and Methods. 66 male mice С57Вl/6 were used in the experiment. A model of subcutaneous growth of B16/F10 melanoma (during 3 weeks) was created in the cnp presence (sciatic nerve ligation). Concentrations of nos-2, nos-3, l-arginine, citrulline, total nitrite, nitrotyrosine and adma were determined by elisa in intact and tumor tissues.Results. A significant increase in levels of no-synthases was revealed in the skin and tumor tissues in the tumor growth with cnp from week 1, as well as a decrease in the level of total nitrite in the skin, multidirectional dynamics of adma and arginine levels, a steadily increased level of citrulline in the skin and tumor in the dynamics of tumor growth with cnp.Conclusions. Male mice with B16 melanoma growing in the presence of cnp demonstrated a more active functioning of the no-system already from week 1, compared to standard tumor growth, which might result in a greater rate of growth of melanoma with cnp. Significantly higher skin and tumor levels of citrulline in males were a distinctive feature, in contrast to melanoma with standard growth, which could be the result of inhibition of arginine synthesis and formation of a tumor auxotrophic for arginine.

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Dorsal Root Ganglion (DRG) and Chronic Pain

Anesthesiology and Pain Medicine ◽

10.5812/aapm.113020 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Amnon A. Berger ◽

Yao Liu ◽

HarLee Possoit ◽

Anna C. Rogers ◽

Warner Moore ◽

...

Keyword(s):

Quality Of Life ◽

Chronic Pain ◽

Neuropathic Pain ◽

Dorsal Root ◽

Randomized Trials ◽

Pain Treatment ◽

Common Condition ◽

Significant Morbidity ◽

Chronic Neuropathic Pain

Context: Chronic neuropathic pain is a common condition, and up to 11.9% of the population have been reported to suffer from uncontrolled neuropathic pain. Chronic pain leads to significant morbidity, lowered quality of life, and loss of workdays, and thus carries a significant price tag in healthcare costs and lost productivity. dorsal root ganglia (DRG) stimulation has been recently increasingly reported and shows promising results in the alleviation of chronic pain. This paper reviews the background of DRG stimulation, anatomical, and clinical consideration and reviews the clinical evidence to support its use. Evidence Acquisition: The DRG span the length of the spinal cord and house the neurons responsible for sensation from the periphery. They may become irritated by direct compression or local inflammation. Glial cells in the DRG respond to nerve injury, producing inflammatory markers and contribute to the development of chronic pain, even after the resolution of the original insult. While the underlying mechanism is still being explored, recent studies explored the efficacy of DRG stimulation and neuromodulation for chronic pain treatment. Results: Several reported cases and a small number of randomized trials were published in recent years, describing different methods of DRG stimulation and neuromodulation with promising results. Though evidence quality is mostly low, these results provide evidence to support the utilization of this technique. Conclusions: Chronic neuropathic pain is a common condition and carries significant morbidity and impact on the quality of life. Recent evidence supports the use of DRG neuromodulation as an effective technique to control chronic pain. Though studies are still emerging, the evidence appears to support this technique. Further studies, including large randomized trials evaluating DRG modulation versus other interventional and non-interventional techniques, are needed to further elucidate the efficacy of this method. These studies are also likely to inform the patient selection and the course of treatment.

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GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, but not in Female Mice

10.1101/2021.04.16.440030 ◽

2021 ◽

Author(s):

Akila Ram ◽

Taylor Edwards ◽

Ashley McCarty ◽

Leela Afrose ◽

Max V McDermott ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Inflammatory Pain ◽

Therapeutic Potential ◽

Periaqueductal Gray ◽

Male Mice ◽

Once Daily ◽

Female Mice ◽

Protein Levels ◽

Thermal Hypersensitivity

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not reduce thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the periaqueductal gray. Treatment with MS15203 then rescued the protein levels of GPR171 in the periaqueductal gray of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.

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Neuropathic pain

Innovative medicine of Kuban ◽

10.35401/2500-0268-2021-22-2-58-64 ◽

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.

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Dorsal Root Ganglion Stimulation for the Management of Chronic Neuropathic Pain: A Retrospective Case Series during Four Years follow-up in a Single Center

The Open Pain Journal ◽

10.2174/1876386302013010035 ◽

2020 ◽

Vol 13 (1) ◽

pp. 35-41

Author(s):

Alfonso Papa ◽

Elisabetta Saracco ◽

Maria Teresa Di Dato ◽

Pietro Buonavolontà ◽

Anna Maria Salzano ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Data Collection ◽

Dorsal Root ◽

Case Series ◽

Chronic Neuropathic Pain ◽

Neuropathic Pain Syndrome

Objectives: The dorsal root ganglion (DRG) is involved in the transduction of pain signals to the central nervous system (CNS) and undergoes a number of physiopathological changes during chronic pain. The purpose of this data collection was to evaluate the long-term safety and efficacy of DRG stimulation for the treatment of chronic pain and its impact on functional aspects. Materials and Methods: Forty-four subjects with non-reactive chronic neuropathic pain syndrome were implanted with DRG stimulation. Patients were evaluated at baseline as well as at 15, and 30 days, and at 3, 6, 12, 24, 36 and 48 months after medical intervention/surgery using the Visual Analogic Scale (VAS), which measures pain intensity, and the Oswestry Scale, for the estimation of disability (ODI). Results: After four years of simulation, VAS and ODI showed a statistically significant reduction throughout the follow-up period. The average pain relief obtained after 48 months of treatment was 74.1% ± 3.4. Conclusion: The results of this data collection demonstrate the feasibility of DRG stimulation, the correspondence between the clinical indications at the DRG implant and what is commonly found in the literature on this technique.(18,20) Patients defined as clinical responders to DRG stimulation and so implanted with definitive IPG showed a sustained and long term efficacy. Eight patients had previously been implanted with a traditional SCS without any clinically relevant efficacy; they were then explained for unsatisfactory results. Six of them (75%) were later implanted with DRG, with long-term effectiveness. Another advantage of this therapy is the absence of positional effects and lead migration. The adverse events proved to be independent of the anatomical level of insertion; moreover, this series of cases show a lower incidence of lead migration than reported in the literature. In summary, DRGs have been ignored for too long, probably due to the technical difficulty of reaching their deep, almost extra-spinal anatomical position.

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GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice

Frontiers in Pain Research ◽

10.3389/fpain.2021.695396 ◽

2021 ◽

Vol 2 ◽

Author(s):

Akila Ram ◽

Taylor Edwards ◽

Ashley McCarty ◽

Leela Afrose ◽

Max V. McDermott ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Inflammatory Pain ◽

Therapeutic Potential ◽

Male Mice ◽

Once Daily ◽

Male And Female ◽

Female Mice ◽

Protein Levels ◽

Thermal Hypersensitivity

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10 mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freund's Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not alleviate thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray (PAG) in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the PAG. Treatment with MS15203 then rescued the protein levels of GPR171 in the PAG of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.

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Recognition of the importance of neuropathic pain epidemiology

10.1093/med/9780198834359.003.0071 ◽

2018 ◽

Author(s):

Matthew Brown

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

General Population ◽

Significant Proportion ◽

Epidemiological Data ◽

Current Treatment ◽

Pecking Order ◽

Chronic Neuropathic Pain ◽

Healthcare Resources ◽

Epidemiology Studies

The landmark paper discussed in this chapter is ‘Prevalence of chronic pain with neuropathic characteristics in the general population’, published by Bouhassira and Lantéri-Minet in 2008. Understanding the extent to which a specific condition affects a population is of great importance, for two main reasons. First, robust epidemiological data influences relevant legislators and policymaking, leading to improvements in the allocation of scarce healthcare resources. Second, epidemiology studies alert clinicians and academics to deficiencies and oversights in current treatment. For decades, chronic pain resided in a twilight world, under-recognized and under-resourced, while patients suffered. Papers such as this pioneering work by Bouhassira and Lantéri-Minet started to turn the tide with respect to chronic pain’s profile in the pathological pecking order. It is important because it demonstrated in unarguable fashion the degree to which chronic neuropathic pain blights the lives of a significant proportion of the population.

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Abstract 302: Chronic Neuropathic Pain Increases Susceptibility to Myocardial Ischemia/Reperfusion Injury by Sirt1 Carbonylative Inactivation

Circulation Research ◽

10.1161/res.121.suppl_1.302 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Chen Li ◽

Jingrun Yang ◽

Lu Yu ◽

Chunhu Gu ◽

Heng Ma

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Myocardial Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Carbonyl Stress ◽

Ampk Activation ◽

Chronic Neuropathic Pain ◽

Myocardial Ischemia Reperfusion ◽

Reactive Aldehyde

Pain is not a symptom that exists alone, but whether chronic pain enhances susceptibility to myocardial ischemia/reperfusion (MI/R) injury and the underlying mechanisms remain unknown. Reactive aldehydes contribute to pain pathologies and cardiac injury, suggesting that aldehyde dehydrogenase (ALDH2), which detoxifies aldehydes, may regulate chronic pain related MI/R injury. In this study, chronic neuropathic pain was induced by chronic compression of the dorsal root ganglion (CCD). CCD for 2 weeks, ALDH2 KO or wild-type (WT) littermates were subjected to in vivo MI/R. CCD-WT mice exhibited heightened nociception and correlated with circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. CCD induced 4-HNE overload provoked cardiac SIRT1 carbonylative inactivation and impairment the cardioprotection of LKB1-mediated AMPK activation, which resulting in enhanced MI/R injury and higher mortality compare with pain free WT mice. Chronic neuropathic pain enhanced susceptibility to MI/R injury was further exacerbated by ALDH2 deficiency in which associated with more impaired SIRT1-LKB1-AMPK signaling. However, treatment of CCD-WT mice with ALDH2-selective activator (Alda-1) or cardiac specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly reduced chronic neuropathic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and elevated cardiac function). These results strongly suggest that elevated reactive aldehyde concentration, like that observed in the presence of chronic pain, may render cardiomyocytes more susceptible to MI/R injury by SIRT1 carbonylative inactivation and impairment the cardioprotection of LKB1-mediated AMPK activation. ALDH2 activation blocked reactive aldehyde overproduction induced carbonyl stress and attenuated myocardial ischemic vulnerability in chronic pain individual. Keywords: chronic pain; myocardial ischemia/reperfusion; ALDH2; 4-HNE; carbonylation

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