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. Allometric conversion of this intraperitoneal morphine dose in mice equals an oral morphine dose of about 146 mg in a 60-kg adult. Our work quantifies for the first time analgesia and antihyperalgesia in an inflammatory pain model after DRG transduction by CA8 gene therapy

A Patient Had LASIK 2 Months Ago and Has Persistent Pain in the Eyes That Does Not Seem to Be Related to Surface Issues or Other Anatomical Abnormalities. How Do I Diagnose and Manage This?

Persistent pain in the eyes after LASIK may be caused by diverse and complex pathophysiological mechanisms that involve interactions between the cornea and somatosensory, optic, and autonomic neural circuits. 1 A sensitized peripheral and central nervous system may be the main contributing factor to pain and sensitivity to light. 2 Not infrequently, various mechanisms coexist, such as in cases of concomitant inflammatory and neuropathic contributors to pain. Yet, in most chronic cases, centralized pain as a result of sensitization and hyperexcitability of central neurons, subsequent to nociceptive input, may further contribute to chronicity and intractability of pain. High prevalence of other chronic painful and/or psychiatric illnesses or cognitive-behavioral abnormalities in patients with pain in the eyes further confound their diagnostic and therapeutic approach. These considerations highlight the need for interdisciplinary diagnostic and therapeutic approaches, involving eye and pain specialists, mental health specialists, physical therapists, and other health professionals

Chapter 16 - Pathways and Mechanisms of Ocular Pain and Photophobia in Dry Eye Disease

The trigeminal nerve gives rise to the corneal nerve system, which plays a crucial role in sensory processing on the ocular surface (touch, pain, and temperature) as well as in healing and homeostasis through release of neuromodulators. Several forms of noxious stimuli can lead to dysfunctions along this pathway, manifesting as disease states such as dry eye disease (DED) characterized by chronic unpleasant ocular symptoms, including pain, discomfort, and photophobia. Ocular pain is part of a multidimensional sensory and emotional experience mediated by complex peripheral and central pathogenetic mechanisms. Different forms of ocular pain exist, including pain due to chronic noxious stimulation at the ocular surface (e.g., nociceptive pain), pain due to corneal nerve dysfunction causing hyperexcitability and sensitizing mechanisms (neuropathic pain), or both. Typically, noxious stimuli activate peripheral nerve terminals and generate signals that are relayed and processed in the spinal trigeminal nucleus of the medulla and then conveyed to the thalamus and other subcortical and cortical areas of the central nervous system. Normally, with removal of the stimulus, pain dissipates in an acute fashion. However, peripheral and central sensitization of neurons (due to spatially and temporally excessive noxious signal traffic, neuroinflammation, and glial activation) can result in hyperexcitability, allowing for chronicity with heightened spontaneous pain and abnormally painful evoked responses to stimuli (allodynia, hyperalgesia, photophobia). This chapter discusses concepts of corneal nerve anatomy and how they relate to ascending pathways of ocular pain and photophobia in DED

Chapter 15 - Treatment of Ocular Pain Not Responsive to Traditional Dry Eye Disease Treatments

Neuropathic ocular pain (NOP) in dry eye disease can be a challenging condition to treat. The pathogenesis of NOP often results from injury to the corneal nerves, leading to neural plasticity and peripheral and central neuronal sensitization. These patients often present with ocular pain, allodynia, photophobia, and neuro-behavioral manifestations and seldom respond to traditional dry eye treatments. For the treatment of NOP, the goal is to use a multimodal approach addressing both the peripheral and centralized pain using a host of topical and systemic therapies. Topical therapies include contact lenses and nerve regenerative therapies such autologous serum tears. Systemic therapies often used for other neuropathic pain conditions can potentially be helpful in NOP; these medications consist of gabapentinoids and other anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors. Further, procedural therapies such as transcutaneous electrical nerve stimulation and peri-orbital nerve blocks may be useful in patients who are refractory to topical and systemic therapies. Lastly, since NOP can have a significant negative impact on quality-of-life measures with regard to mood, sleep, activity, adjunctive behavioral therapy may be beneficial. Ultimately, a personalized multimodal therapy will often be necessary to address the complex mechanisms underlying NOP

Neuropathic ocular surface pain: Emerging drug targets and therapeutic implications

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. This review will examine studies focusing on ocular surface pain, emphasizing those examining patients with a neuropathic component. Attention will be placed toward recent (after 2017) studies that have examined new and emerging therapies for neuropathic ocular surface pain. Several therapies have been studied thus far, and continued research is needed to identify which individuals would benefit from specific therapies. Gaps in our understanding exist, especially with availability of in-clinic diagnostics for neuropathic pain. A focus on improving diagnostic capabilities and researching gene-modulating therapies could help us to provide more specific mechanism-based therapies for patients. In the meantime, continuing to uncover new modalities and examining which are likely to work depending on pain phenotype remains an important short-term goa

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

To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs. 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. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch. The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate-severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate-severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms. Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity

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. Symptoms and signs of DE were assessed, and tear samples was analyzed by mass spectrometry–based lipidomics. Statistical analyses comparing the relationship between tear film lipids and DE included Pearson/Spearman correlations and t-tests. RESULTS: Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were present in more than 90% of tear film samples. The ratio of ω-6 (AA) to ω-3 (DHA+EPA) fatty acids was correlated with multiple measures of tear film dysfunction (tear breakup time, Schirmer 2 scores, and corneal staining; all P < 0.05). Arachidonic acid–derived prostaglandin E(2) was detected in the majority of samples and correlated with low tear osmolarity, meibomian gland plugging, and corneal staining. CONCLUSIONS: Both ω-3 and ω-6 lipid circuits are activated in the human tear film. The ratio of ω-6:ω-3 tear lipids is elevated in DE patients in proportion to the degree of tear film dysfunction and corneal staining. Metabolic deficiency of ω-3 tear film lipids may be a driver of chronic ocular surface inflammation in DE

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. 101 individuals seen at the University of Miami Oculofacial Pain Clinic from January 2015 to August 2021 with ≥3 months of clinically diagnosed neuropathic pain were included. Patients were subcategorized (postsurgical, post-traumatic, migraine-like, and laterality) and self-reported treatment outcomes were assessed (no change, mild, moderate, or marked improvement). One-way ANOVA (analysis of variance) was used to examine relationships between follow up time and number of treatments attempted with pain improvement, and multivariable logistic regression was used to assess which modalities led to pain improvement. The mean age was 55 years, and most patients were female (64.4%) and non-Hispanic (68.3%). Migraine-like pain (40.6%) was most common, followed by postsurgical (26.7%), post-traumatic (16.8%) and unilateral pain (15.8%). The most common oral therapies were α2δ ligands (48.5%), the m common topical therapies were autologous serum tears (20.8%) and topical corticosteroids (19.8%), and the most common adjuvant was periocular nerve block (24.8%). Oral therapies reduced pain in post-traumatic (81.2%), migraine-like (73%), and unilateral (72.7%) patients, but only in a minority of postsurgical (38.5%) patients. Similarly, topicals improved pain in post-traumatic (66.7%), migraine-like (78.6%), and unilateral (70%) compared to postsurgical (43.7%) patients. Non-oral/topical adjuvants reduced pain in postsurgical (54.5%), post-traumatic (71.4%), and migraine-like patients (73.3%) only. Multivariable analyses indicated migraine-like pain improved with concomitant oral α2δ ligands and adjuvant therapies, while postsurgical pain improved with topical anti-inflammatories. Those with no improvement in pain had a shorter mean follow-up (266.25 ± 262.56 days) than those with mild (396.65 ± 283.44), moderate (652 ± 413.92), or marked improvement (837.93 ± 709.35) ( < 0.005). Identical patterns were noted for number of attempted medications. Patients with migraine-like pain frequently experienced pain improvement, while postsurgical patients had the lowest response rates. Patients with a longer follow-up and who tried more therapies experienced more significant relief, suggesting multiple trials were necessary for pain reduction

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.sup.G) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204.sup.G expression vector also produced a stable 1697 bp transcript (CA8-204.sup.C) coding for a smaller peptide (~22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro and produced profound analgesia in vivo. This is the first report showing CA8-204.sup.C codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia. Author Affiliation: (1) Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, USA (2) Department of Anesthesiology, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada (3) Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA (4) John T. MacDonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA (5) John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA (6) Department of Anesthesiology, Center for Translational Pain Medicine, Duke University School of Medicine, Durham, NC, USA (7) University of Miami Miller School of Medicine, Rosenstiel Medical Sciences Building - Room 8010A (R-371), 33136, Miami, FL, USA (k) [email protected] Article History: Registration Date: 09/18/2020 Received Date: 07/01/2020 Accepted Date: 09/18/2020 Online Date: 11/28/2020 Byline:Academi

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

ObjectiveTo 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.DesignCross-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). This was followed by a comprehensive ocular surface examination. The patients' comorbidities, medications, mental health (depression and post-traumatic stress disorder) and quality-of-life indices were also obtained. Patients were classified using cluster analysis into either the ‘high NOP’ or ‘low NOP’ group. Subsequent analyses were performed to examine differences in ocular and non-ocular parameters between these two groups.ResultsDespite similar ocular surface findings, patients in the high NOP group had very different systemic (non-ocular) profiles with higher overall pain intensity ratings, higher frequency of comorbid chronic centralised pain conditions, lower quality-of-life indices and more abnormal mental health scores than those in the low NOP group.ConclusionsConsistent with a chronic overlapping pain condition, patients with DE disease with more severe NOP symptoms report more frequent and severe non-ocular functional comorbid pain disorders