Disease-modifying rdHSV-CA8* non-opioid analgesic gene therapy treats chronic osteoarthritis pain by activating Kv7 voltage-gated potassium channels.

Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis () is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of quality-adjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector () incorporating a modified carbonic anhydrase-8 transgene () produces analgesia and treats monoiodoacetate-induced () chronic knee pain due to OA.

rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels.

Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability.

Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model.

Background: Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats.

Impact of Tumor Necrosis Factor Receptor 1 () Polymorphism on Dry Eye Disease.

The goal of the study was to examine whether a genetic polymorphism in tumor necrosis factor receptor 1 () gene impacted the dry eye disease (DED) phenotype and response to anti-inflammatory therapy. The prospective study included 328 individuals with various dry eye (DE) symptoms and signs recruited from the Miami Veterans Hospital eye clinic between October 2013 and October 2017. The population underwent genetic profiling for a polymorphism within the gene (rs1800693 [TT, TC, CC]).

Role of Tumor Necrosis Factor Receptor 1-Reactive Oxygen Species-Caspase 11 Pathway in Neuropathic Pain Mediated by HIV gp120 With Morphine in Rats.

Background: Recent clinical research suggests that repeated use of opioid pain medications can increase neuropathic pain in people living with human immunodeficiency virus (HIV; PLWH). Therefore, it is significant to elucidate the exact mechanisms of HIV-related chronic pain. HIV infection and chronic morphine induce proinflammatory factors, such as tumor necrosis factor (TNF)α acting through tumor necrosis factor receptor I (TNFRI).

Differential Effects of Treatment Strategies in Individuals With Chronic Ocular Surface Pain With a Neuropathic Component.

Dysfunction at the ocular system via nociceptive or neuropathic mechanisms can lead to chronic ocular pain. While many studies have reported on responses to treatment for nociceptive pain, fewer have focused on neuropathic ocular pain. This retrospective study assessed clinical responses to pain treatment modalities in individuals with neuropathic component ocular surface pain.

Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo.

Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3.

Periorbital botulinum toxin A improves photophobia and sensations of dryness in patients without migraine: Case series of four patients.

Purpose: Individuals receiving botulinum toxin A (BoNT-A) injections in the head and neck for migraine treatment have reported decreases in photophobia and sensations of dryness, independent of ocular surface parameters. We hypothesized that patients without migraine but with similar ocular neuropathic-like symptoms would also experience symptomatic improvement with periocular BoNT-A injections, independent of ocular surface changes.

Observations: We identified four individuals without a history of migraine but with neuropathic ocular pain (symptoms of dryness, burning, and photophobia that were out of proportion to ocular surface findings and unresponsive to ongoing dry eye (DE) therapies).

Transcutaneous Electrical Nerve Stimulation for the Long-Term Treatment of Ocular Pain.

Purpose: Ocular pain is a debilitating condition that is challenging to treat as therapies that target the ocular surface are often ineffective. We previously reported a short-term reduction in ocular pain after one periocular transcutaneous electrical nerve stimulation (TENS) session. The current study aims to elucidate the long-term effect of TENS on ocular pain.

Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain.

Purpose: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain.

Methods: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation.

The Genetics of Neuropathic Pain from Model Organisms to Clinical Application.

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling.

Pregabalin Failed to Prevent Dry Eye Symptoms after Laser-Assisted in Situ Keratomileusis (LASIK) in a Randomized Pilot Study.

Purpose: Perioperative pregabalin administration has been found to reduce the risk of persistent pain after a variety of surgical procedures. However, this approach has not been tested in relation to eye surgery. As such, the purpose of this study was to evaluate whether perioperative pregabalin can reduce the presence of dry eye (DE) symptoms, including eye pain, six months after laser-assisted in situ keratomileusis (LASIK).

Dysfunctional Coping Mechanisms Contribute to Dry Eye Symptoms.

Dysfunctional coping behaviors, such as catastrophizing, have been implicated in pain severity and chronicity across several pain disorders. However, the impact of dysfunctional coping has not been examined under the context of dry eye (DE). This study evaluates relationships between catastrophizing and measures of DE, including pain severity and pain-related daily interference.

Oral Gabapentinoids and Nerve Blocks for the Treatment of Chronic Ocular Pain.

Purpose: There is a recognition that nerve dysfunction can contribute to chronic ocular pain in some individuals. However, limited data are available on how to treat individuals with a presumed neuropathic component to their ocular pain. As such, the purpose of this study was to examine the efficacy of our treatment approaches to this entity.

Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.

Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.

Individuals with migraine have a different dry eye symptom profile than individuals without migraine.

Background: Many individuals with migraine report symptoms of dry eye (DE). However, it is not known whether DE profiles are similar between individuals with and without migraine. To bridge this gap, we evaluated symptoms and signs of DE, including symptoms suggestive of nerve dysfunction, in a large group of individuals with DE symptoms, and compared profiles between individuals with migraine and those without migraine or headache.

Modification of the Neuropathic Pain Symptom Inventory for use in eye pain (NPSI-Eye).

Chronic eye pain, which has previously been assumed to be due to ocular surface abnormalities (ie, "dry eye [DE] disease"), has recently garnered attention as a potential indicator of neuropathic ocular pain in some patients. The purpose of this study was to evaluate the psychometric properties of a modified version of the Neuropathic Pain Symptom Inventory in individuals with eye pain (NPSI-Eye). Enrolled participants (n = 397) completed the NPSI-Eye, general pain severity questionnaires, DE symptom report, and psychological health indices.

Resolution of pain with periocular injections in a patient with a 7-year history of chronic ocular pain.

Purpose: We report a case of a male patient with chronic ocular pain that resolved completely following peripheral nerve blocks.

Observations: A 66-year-old male presented with a seven-year history of severe left eye pain and photophobia. The pain began after retinal detachment repair with scleral buckle placement.

Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections.

Background: To evaluate the efficacy of botulinum toxin A (BoNT-A) in reducing photophobia and dry eye symptoms in individuals with chronic migraine. Additionally, we aimed to evaluate tear film volume as a potential contributor to symptoms in these patients.

Methods: Retrospective review of 76 patients who received BoNT-A for chronic migraine between 23 August 2017 and 13 December 2017 at the Miami Veterans Affairs Medical Center Neurotoxin Clinic.

Epidemiology of Persistent Postsurgical Pain Manifesting as Dry Eye-Like Symptoms After Cataract Surgery.

Purpose: To evaluate the epidemiology of persistent postsurgical pain (PPP) manifesting as dry eye (DE)-like symptoms 6 months after surgery.

Methods: This single-center study included 119 individuals whose cataract surgeries were performed by a single surgeon at the Bascom Palmer Eye Institute and who agreed to participate in a phone survey 6 months after surgery. Patients were divided into 2 groups: the PPP group was defined as those with a Dry Eye Questionnaire-5 score ≥6 and without PPP as those with a Dry Eye Questionnaire-5 score <6 at 6 months after cataract surgery.

Human carbonic anhydrase-8 AAV8 gene therapy inhibits nerve growth factor signaling producing prolonged analgesia and anti-hyperalgesia in mice.

Carbonic anhydrase-8 (Car8; murine gene symbol) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates neuronal intracellular calcium release. We previously reported that wild-type Car8 overexpression corrects the baseline allodynia and hyperalgesia associated with calcium dysregulation in the waddle (wdl) mouse due to a 19 bp deletion in exon 8 of the Car8 gene. In this report, we provide preliminary evidence that overexpression of the human wild-type ortholog of Car8 (CA8), but not the reported CA8 S100P loss-of-function mutation (CA8), inhibits nerve growth factor (NGF)-induced phosphorylation of ITPR1, TrkA (NGF high-affinity receptor), and ITPR1-mediated cytoplasmic free calcium release in vitro.

Epidemiology of Persistent Dry Eye-Like Symptoms After Cataract Surgery.

Purpose: To evaluate the frequency and risk factors for persistent postsurgical pain (PPP) after cataract surgery, defined as mild or greater dry eye (DE)-like symptoms 6 months after surgery.

Methods: This single-center study included 86 individuals who underwent cataract surgery between June and October 2016 and had DE symptom information available 6 months after surgery. Patients were divided into 2 groups: controls were defined as those without DE symptoms 6 months after surgery (defined by a Dry Eye Questionnaire 5 (DEQ5) score <6), cases were defined as those with mild or greater DE-like symptoms 6 months after surgery (DEQ5 ≥6).

Evidence that dry eye is a comorbid pain condition in a U.S. veteran population.

Introduction: Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions.

Objectives: To evaluate DE as a comorbid condition in the U.S.