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.

Chemical toxic exposures and chronic ocular pain.

Chronic ocular pain is a common, debilitating chronic pain condition with significant morbidity and negative impact in patients' quality of life. Several, diverse types of insults to the ocular surface can lead to acute, and under certain conditions to chronic ocular pain, and these include toxic irritants. Exposure of ocular surface to toxic irritants, in addition to direct tissue injury, carries the capacity to generated intense immune and neuronal responses with hyper-excitability, sensitization and chronic pain.

Neuropathic ocular surface pain: Emerging drug targets and therapeutic implications.

Introduction: Dysfunction at various levels of the somatosensory system can lead to ocular surface pain with a neuropathic component. Compared to nociceptive pain (due to noxious stimuli at the ocular surface), neuropathic pain tends to be chronic and refractory to therapies, making it an important source of morbidity in the population. An understanding of the options available for neuropathic ocular surface pain, including new and emerging therapies, is thus an important topic.

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.

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.

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.

The Relationship Between Ocular Itch, Ocular Pain, and Dry Eye Symptoms (An American Ophthalmological Society Thesis).

Purpose: To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs.

Methods: A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing.

Neuropathic pain and dry eye.

Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. Its epidemiology and clinical presentation have many similarities with neuropathic pain outside the eye. This review highlights the similarities between dry eye and neuropathic pain, focusing on clinical features, somatosensory function, and underlying pathophysiology.

Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice.

Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice.

Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice.

Carbonic anhydrase-8 (Car8 mouse gene symbol) is devoid of enzymatic activity, but instead functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) to regulate this intracellular calcium release channel important in synaptic functions and neuronal excitability. Causative mutations in ITPR1 and carbonic anhydrase-8 in mice and humans are associated with certain subtypes of spinal cerebellar ataxia (SCA). SCA mice are genetically deficient in dorsal root ganglia (DRG) Car8 expression and display mechanical and thermal hypersensitivity and susceptibility to subacute and chronic inflammatory pain behaviors.

Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain.

Objective: To evaluate how closely neuropathic-like ocular pain (NOP) symptoms align with a metric of central sensitisation (ie, the presence of persistent ocular pain after topical anaesthetic placement) in individuals with dry eye (DE) symptoms.

Design: Cross-sectional study of 224 individuals with DE symptoms seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding DE symptoms, NOP descriptors and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing.

ω-3 Tear Film Lipids Correlate With Clinical Measures of Dry Eye.

Purpose: ω-3 and ω-6 polyunsaturated fatty acids modulate inflammatory processes throughout the body through distinct classes of lipid mediators that possess both proinflammatory and proresolving properties. The purpose of this cross-sectional study was to explore the relationship between lipid profiles in human tears and dry eye (DE) symptoms and signs.

Methods: Forty-one patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration Hospital over 18 months.

Patients with more severe symptoms of neuropathic ocular pain report more frequent and severe chronic overlapping pain conditions and psychiatric disease.

Objective: To study chronic pain and mental health profiles in patients with dry eye (DE) symptoms, comparing those with high and low levels of neuropathic ocular pain (NOP) complaints.

Design: Cross-sectional study of 181 patients with DE symptoms (dry eye questionnaire score ≥6) seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding DE symptoms, NOP complaints (burning, sensitivity to wind, light and cold/hot temperatures) and pain elsewhere in the body (non-ocular).

Dry Eye Profiles in Patients with a Positive Elevated Surface Matrix Metalloproteinase 9 Point-of-Care Test Versus Negative Patients.

Purpose: To compare dry eye (DE) symptoms and signs in subjects who tested positive versus those who tested negative for ocular surface matrix metalloproteinase 9 (MMP-9) using the InflammaDry point-of-care test (RPS, Sarasota, FL).

Methods: In this cross-sectional study, individuals seen in the Miami Veterans Affairs eye clinic with DE symptoms, as evidenced by DE questionnaire 5 (DEQ5) ≥6, were given standardized questionnaires to assess DE symptoms and ocular and non-ocular pain complaints. Also, a complete evaluation was conducted to measure ocular surface signs of DE.

Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes.

Unlabelled: Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS.

Incomplete response to artificial tears is associated with features of neuropathic ocular pain.

Aims: Artificial tears are first-line therapy for patients with dry eye symptoms. It is not known, however, which patient factors associate with a positive response to therapy. The purpose of this study was to evaluate whether certain ocular and systemic findings are associated with a differential subjective response to artificial tears.

Chronic dry eye symptoms after LASIK: parallels and lessons to be learned from other persistent post-operative pain disorders.

Laser in-situ keratomileusis (LASIK) is a commonly performed surgical procedure used to correct refractive error. LASIK surgery involves cutting a corneal flap and ablating the stroma underneath, with known damage to corneal nerves. Despite this, the epidemiology of persistent pain and other long-term outcomes after LASIK surgery are not well understood.

Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington's disease, Alzheimer's, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors.

Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain.

Objective: Studies of patients with non-ocular pain suggest that it is therapeutically useful to identify those with features of neuropathic pain. No data is available, however, on whether this approach has similar utility in dry eye. The purpose of this study was to determine whether severity and persistence of dry eye symptoms associate with self-reported symptoms of neuropathic ocular pain (NOP).