Face-down positioning or posturing after pars plana vitrectomy for macula-involving rhegmatogenous retinal detachments.

BACKGROUND: A macula-involving rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic surgical emergencies and causes significant visual morbidity. Pars plana vitrectomy (PPV) with gas tamponade is often performed to repair primary macula-involving RRDs with a high rate of anatomical retinal reattachment. It has been advocated by some ophthalmologists that face-down positioning after PPV and gas tamponade helps reduce postoperative retinal displacement. Retinal displacement can cause metamorphopsia and binocular diplopia. OBJECTIVES: The primary objective of this review is to determine whether face-down positioning reduces the risk of retinal displacement following PPV and gas tamponade for primary macula-involving RRDs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 11), MEDLINE (January 1946 to 28 November 2022), Embase.com (January 1947 to 28 November 2022), PubMed (1948 to 28 November 2022), Latin American and Caribbean Health Sciences Literature database (1982 to 28 November 2022), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 28 November 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which face-down positioning was compared with no positioning or another form of positioning following PPV and gas tamponade for primary macula-involving RRDs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for the prespecified outcomes using the GRADE approach. MAIN RESULTS: We identified three RCTs (369 eyes of 368 participants) that met the eligibility criteria. Two RCTs provided data on postoperative retinal displacement, one reported on postoperative distortion and quality of life outcomes, two on postoperative best-corrected visual acuity (BCVA) in logMAR, and two on postoperative ocular adverse events such as outer retinal folds. Study characteristics and risk of bias All the trials involved predominantly male participants (range: 68% to 72%). Only one trial provided race and ethnicity information, was registered on a trial registry, and reported funding sources. Using the RoB 2 tool, we assessed the risk of bias for proportion of eyes with retinal displacement, mean change in visual acuity, objective distortion scores, quality of life assessments, and ocular adverse events, with most domains judged to be at low risk of bias. Findings Immediate face-down positioning may result in a lower proportion of participants with postoperative retinal displacement compared with support-the-break positioning at six months (risk ratio [RR] 0.73, 95% confidence interval [CI] 0.54 to 0.99; 1 RCT; 239 eyes of 239 participants; very low certainty evidence). One study found no evidence of a difference in BCVA at three months when comparing postoperative face-up with face-down positioning with or without perfluorocarbon liquid (mean difference [MD] -0.03, 95% CI -0.09 to 0.02; I2 = 0; 56 eyes of 56 participants; very low certainty evidence). Immediate face-down positioning appears to have little to no effect on postoperative distortion scores at week 26 (MD 1.80, 95% CI -1.92 to 5.52; 1 RCT; 219 eyes of 219 participants; very low certainty evidence) and postoperative quality of life assessment scores at week 26 (MD -1.80, 95% CI -5.52 to 1.92; 1 RCT; 217 eyes of 217 participants; very low certainty evidence). Adverse events One study that enrolled 262 participants with macula-involving RRDs suggested that immediate face-down positioning after PPV and gas tamponade may reduce the ocular adverse event of postoperative outer retinal folds at six months (RR 0.39, 95% CI 0.17 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) and binocular diplopia (RR 0.20, 95% CI 0.04 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) compared with support-the-break positioning. Immediate face-down positioning may increase the ocular adverse event of elevated intraocular pressure compared with support-the-break positioning (RR 1.74, 95% CI 1.11 to 2.73; 1 RCT; 262 eyes of 262 participants; very low certainty evidence). Another study found no evidence of a difference in postoperative outer retinal folds when comparing face-down versus face-up positioning at one and three months (RR 1.00, 95% CI 0.50 to 2.02; RR 1.00, 95% CI 0.28 to 3.61; 1 RCT; 56 eyes of 56 participants; very low certainty evidence). No studies reported non-ocular adverse events. AUTHORS' CONCLUSIONS: Very low certainty evidence suggests that immediate face-down positioning after PPV and gas tamponade may result in a reduction in postoperative retinal displacement, outer retinal folds, and binocular diplopia, but may increase the chance of postoperative raised intraocular pressure compared with support-the-break positioning at six months. We identified two ongoing trials that compare face-down positioning with face-up positioning following PPV and gas tamponade in participants with primary macula-involving RRDs, whose results may provide relevant evidence for our stated objectives. Future trials should be rigorously designed, and investigators should analyze outcome data appropriately and report adequate information to provide evidence of high certainty. Quality of life and patient preferences should be examined in addition to clinical and adverse event outcomes.

Artificial intelligence using deep learning to predict the anatomical outcome of rhegmatogenous retinal detachment surgery: a pilot study.

PURPOSE: To develop and evaluate an automated deep learning model to predict the anatomical outcome of rhegmatogenous retinal detachment (RRD) surgery. METHODS: Six thousand six hundred and sixty-one digital images of RRD treated by vitrectomy and internal tamponade were collected from the British and Eire Association of Vitreoretinal Surgeons database. Each image was classified as a primary surgical success or a primary surgical failure. The synthetic minority over-sampling technique was used to address class imbalance. We adopted the state-of-the-art deep convolutional neural network architecture Inception v3 to train, validate, and test deep learning models to predict the anatomical outcome of RRD surgery. The area under the curve (AUC), sensitivity, and specificity for predicting the outcome of RRD surgery was calculated for the best predictive deep learning model. RESULTS: The deep learning model was able to predict the anatomical outcome of RRD surgery with an AUC of 0.94, with a corresponding sensitivity of 73.3% and a specificity of 96%. CONCLUSION: A deep learning model is capable of accurately predicting the anatomical outcome of RRD surgery. This fully automated model has potential application in surgical care of patients with RRD.

Diabetic retinopathy for the non-ophthalmologist.

Diabetic retinopathy is a microangiopathy resulting from the chronic effects of diabetes mellitus. Healthcare professionals often work in isolation to deliver highly specialised care efficiently and effectively for people living with diabetes. It is not uncommon for people with diabetes to be making frequent visits to community and hospital clinics to see a variety of specialists and healthcare professionals, with seemingly little opportunity for coordination of this complex health management programme between the wider team. In a field that is so diverse and rapidly changing, healthcare professionals of all specialties need to be aware of developments across all aspects of diabetes management. In this article, we discuss the epidemiology and natural history of diabetic retinopathy and describe an approach to its assessment and diagnosis. We provide an overview of the principles of diabetic retinopathy management and outline possible future treatments for diabetic retinopathy.

Therapeutic Effect and Mechanisms of Essential Oils in Mood Disorders: Interaction between the Nervous and Respiratory Systems.

Essential oils (EOs) are extracted from plants and contain active components with therapeutic effects. Evidence shows that various types of EOs have a wide range of health benefits. In our previous studies, the potential of lavender EO for prevention and even treatment of depression and anxiety symptoms was demonstrated. The favourable outcomes may be due to multiple mechanisms, including the regulation of monoamine level, the induction of neurotrophic factor expression, the regulation of the endocrine system and the promotion of neurogenesis. The molecules of EOs may reach the brain and exert an effect through two distinctive pathways, namely, the olfactory system and the respiratory system. After inhalation, the molecules of the EOs would either act directly on the olfactory mucosa or pass into the respiratory tract. These two delivery pathways suggest different underlying mechanisms of action. Different sets of responses would be triggered, such as increased neurogenesis, regulation of hormonal levels, activation of different brain regions, and alteration in blood biochemistry, which would ultimately affect both mood and emotion. In this review, we will discuss the clinical effects of EOs on mood regulation and emotional disturbances as well as the cellular and molecular mechanisms of action. Emphasis will be put on the interaction between the respiratory and central nervous system and the involved potential mechanisms. Further evidence is needed to support the use of EOs in the clinical treatment of mood disturbances. Exploration of the underlying mechanisms may provide insight into the future therapeutic use of EO components treatment of psychiatric and physical symptoms.

A new hypertonic saline assay for analgesic screening in mice: effects of animal strain, sex, and diurnal phase.

PURPOSE: There exists a pressing need for the identification of novel analgesics. We recently reported on a new preclinical assay for rapid analgesic screening based on intraplantar (i.pl.) injection of 10% hypertonic saline (HS) in female outbred (CD-1) mice. Herein, we characterized the HS assay's performance in inbred (C57BL/6) mice, sensitivity to sex differences, and effects of diurnal rhythm phase. METHODS: In randomized, controlled, blinded in vivo animal experiments, we studied nociceptive responses induced by i.pl. HS in C57BL/6 (vs CD-1) mice of both sexes (n = 240) and determined diurnal rhythm phase effects in female animals. We established the HS assay's sensitivity to morphine by constructing dose-response curves and calculating half-maximal inhibitory doses (ID50s). RESULTS: The injection of i.pl. HS produced nociceptive (licking and biting) responses in all C57BL/6 mice tested. In both C57BL/6 and CD-1 mice, the mean (95% confidence interval [CI]) response magnitudes were greater in females vs males (C57BL/6: 87 sec [64 to 110] vs 45 sec [29 to 61]; difference in means, 42 sec; 95% CI, 17 to 68; P < 0.001; n = 10/group; CD-1: 110 sec [95 to 126] vs 53 sec [32 to 74]; difference in means, 57 sec; 95% CI, 34 to 79; P < 0.001; n = 10/group). The mean (95% CI) nociceptive responses were greater at 24:00 hr than at 12:00 hr in C57BL/6 mice (64 sec [40 to 88] vs 37 sec [24 to 51]; difference in means, 27 sec; 95% CI, 7 to 47; P = 0.007; n = 10/group), but not in CD-1 mice (P = 0.97). Intravenous morphine dose-dependently attenuated nociceptive responses of both C57BL/6 and CD-1 mice (ID50, 0.6 and 2.5 mg·kg-1, respectively; P = 0.41). CONCLUSION: These findings in inbred and outbred mice solidify the utility of the HS assay as an effective, rapid, robust, and versatile preclinical tool for analgesic screening.

RéSUMé: OBJECTIF: Il existe un besoin impérieux d'identification de nouveaux analgésiques. Nous avons récemment publié les conclusions d'un nouveau test préclinique portant sur le dépistage analgésique rapide basé sur l'injection intraplantaire (i.pl.) d'une solution saline hypertonique à 10 % (HS) chez des souris femelles croisées (CD-1). Dans notre présente étude, nous avons caractérisé la performance du test de HS chez des souris consanguines (C57BL/6), la sensibilité aux différences de sexe, et les effets des phases de rythme diurne. MéTHODE: Dans le cadre d'expériences animales in vivo en aveugle randomisées contrôlées, nous avons étudié les réponses nociceptives induites par une i.pl. de HS chez des souris C57BL/6 (vs CD-1) des deux sexes (n = 240) et déterminé les effets des phases du rythme diurne chez les animaux femelles. Nous avons établi la sensibilité du test HS à la morphine en construisant des courbes de dose-réponse et en calculant des doses inhibitrices semi-maximales (DI50). RéSULTATS: L'injection i.pl. de HS a produit des réponses nociceptives (léchage et morsure) chez toutes les souris C57BL/6 testées. Chez les souris C57BL/6 et CD-1, les magnitudes de réponse moyenne [intervalle de confiance (IC) 95 %] étaient plus élevées chez les femelles que chez les mâles (C57BL/6 : 87 [64 à 110] vs 45 [29 à 61] sec; différence de moyennes, 42 sec; IC 95 %, 17 à 68; P < 0,001; n = 10/groupe; CD-1: 110 [95 à 126] vs 53 [32 à 74] sec; différence de moyennes, 57 sec; IC 95 %, 34 à 79; P < 0,001; n = 10/groupe). Les réponses nociceptives moyennes [IC 95 %] étaient plus importantes à minuit (24 h) qu'à midi (12 h) chez les souris C57BL/6 (64 [40 à 88] sec vs 37 [24 à 51] sec; différence de moyennes, 27 sec; IC 95 %, 7 à 47; P = 0,007; n = 10/groupe), mais pas chez les souris CD-1 (P = 0,97). La morphine intraveineuse a atténué de façon dose-dépendante les réponses nociceptives chez les souris C57BL/6 et CD-1 (DI50, 0,6 et 2,5 mg·kg−1, respectivement; P = 0,41). CONCLUSION: Ces résultats chez les souris croisées et consanguines appuient l'utilité du test de HS comme un outil préclinique efficace, rapide, robuste et polyvalent pour le dépistage analgésique.

Retinal imaging in infants.

Digital retinal imaging is at the core of a revolution that is continually improving the screening, diagnosis, documentation, monitoring, and treatment of infant retinal diseases. Historically, imaging the retina of infants had been limited and difficult to obtain. Recent advances in photographic instrumentation have significantly improved the ability to obtain high quality multimodal images of the infant retina. These include color fundus photography with different camera angles, ultrasonography, fundus fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. We provide a summary of the current literature on retinal imaging in infants and highlight areas where further research is required.

The acute effects of cigarette smoke exposure on muscle fiber type dynamics in rats.

Reduced exercise capacity is common in people with chronic obstructive pulmonary diseases (COPD) and chronic smokers and is suggested to be related to skeletal muscle dysfunction. Previous studies using human muscle biopsies have shown fiber-type shifting in chronic smokers particularly those with COPD. These results, however, are confounded with aging effects because people with COPD tend to be older. In the present study, we implemented an acute 7-day cigarette smoke-exposed model using Sprague-Dawley rats to evaluate early effects of cigarette smoking on soleus muscles. Rats (n = 5 per group) were randomly assigned to either a sham air (SA) or cigarette smoking (CS) groups of three different concentrations of total particulate matters (TPM) (CSTPM2.5, CSTPM5, CSTPM10). Significantly lower percentages of type I and higher type IIa fiber were detected in the soleus muscle in CS groups when compared with SA group. Of these, only CSTMP10 group exhibited significantly lower citrate synthase activity and higher muscle tumor necrosis factor-α level than that of SA group. Tumor necrosis factor-α level was correlated with the percentage of type I and IIa fibers. However, no significant between-group differences were found in fiber cross-sectional area, physical activities, or lung function assessments. In conclusion, acute smoking may directly trigger the onset of glycolytic fiber type shift in skeletal muscle independent of aging.

A pharmacological characterization of Cannabis sativa chemovar extracts.

BACKGROUND: Cannabis contains Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) as the primary constituents responsible for pharmacological activity. However, there are numerous additional chemically-related structures to Δ9-THC and CBD that are pharmacologically active and may influence the pharmacological properties of Δ9-THC and CBD. This study chemically characterized the cannabinoid constituents in a series of cannabis chemovar extracts and investigated the potential cannabinoid entourage effect in two behavioral assays. METHODS: Six chemovar extracts were compared to pure Δ9-THC, CBD and morphine for effects on the following behavioral assays in mice: hot plate and tail suspension. The battery of behavioral tests was conducted post intravenous administration of cannabis chemovar extract. Cannabinoid profiles of extracts were analyzed using high performance liquid chromatography. Cannabis extracts were administered at equal doses of Δ9-THC to investigate the role of their cannabinoid profiles in modulating the effects of Δ9-THC. Dose response curves were fit using a log[inhibitor] vs response three parameter model and differences between group means were determined using a one-way ANOVA followed by a post hoc test. RESULTS: Cannabis chemovars tested in this study exhibited substantially different cannabinoid profiles. All chemovars produced dose-dependent immobility in the tail suspension assay and dose-dependent antinociception in the hot plate assay. The maximum antinociceptive effect and ED50 was comparable between cannabis chemovars and Δ9-THC. Two cannabis chemovars produced significantly greater immobility in the tail suspension test, with no significant differences in ED50. CONCLUSIONS: Commercially available cannabis chemovars vary widely in cannabinoid content, but when equalized for Δ9-THC content, they produce similar behavioral effects with two exceptions. These findings provide only limited support for the entourage hypothesis. Further studies are necessary to characterize the nature of these pharmacological differences between cannabis chemovars and pure Δ9-THC.

Social and cultural construction processes involved in HPV vaccine hesitancy among Chinese women: a qualitative study.

BACKGROUND: HPV vaccine is a prophylactic vaccine to prevent HPV infections. Recommended by the World Health Organization, this vaccine is clinically proven to be one of the most effective preventive measures against the prevalence of cervical cancer and other HPV-associated cancers and chronic genital conditions. However, its uptake rate among women in Hong Kong is insignificant-only approximately 2.9% adolescent girls and 9.7% female university students received HPV vaccination in 2014. With the notion of Critical Medical Anthropology, we aimed to identify if different influential factors, ranging from individual, societal, and cultural, are involved in the decision-making process of whether to receive HPV vaccination. METHODS: We adopted a qualitative approach and conducted in-depth individual semistructured interviews with 40 women in Hong Kong between May and August 2017. RESULTS: We noted that the following factors intertwined to influence the decision-making process: perceptions of HPV and HPV vaccine; perceived worthiness of HPV vaccines, which was in turn influenced by vaccine cost, marriage plans, and experiences of sexual activities; history of experiencing gynecological conditions, stigma associated with HPV vaccination, acquisition of information on HPV vaccines, distrust on HPV vaccines, and absence of preventive care in the healthcare practice. CONCLUSIONS: HPV vaccination is promoted in a manner that is "feminized" and "moralized" under the patriarchal value system, further imposing the burden of disease on women, and leading to health inequality of women in pursuing the vaccination as a preventive health behaviour as a result. We believe that this ultimately results in an incomplete understanding of HPV, consequently influencing the decision-making process. The "mixed-economy" medical system adopting capitalist logic also molds a weak doctor-patient relationship, leading to distrust in private practice medical system, which affects the accessibility of information regarding HPV vaccination for participants to make the decision.

Lavender essential oil ameliorates depression-like behavior and increases neurogenesis and dendritic complexity in rats.

Depression is a major health issue that causes severe societal economic and health burden. Aromatherapy, a practice that uses essential oils for preventive and therapeutic purposes, represents a promising therapeutic alternative for the alleviation of depressive symptoms. Lavender essential oil (LEO) has been the focus of clinical studies due to its positive effect on mood. An animal model of chronic administration of high dose corticosterone to induce depression- and anxiety-like behavior and reduced neurogenesis was used to explore the biological changes brought by aromatherapy. Twenty-four adult male Sprague Dawley rats were randomly assigned into four groups: Control, corticosterone (Cort) group with high dose of corticosterone, LEO group with daily exposure to LEO by inhalation, and LEO + Cort. At the end of the 14-day treatment period, behavioral tests were carried out. Serum samples were collected 2-3 days after the 14-day period treatment and before perfusion to carry out biochemical analyses to measure BDNF, corticosterone and oxytocin. After perfusion, brains were collected for immunohistochemical analysis to detect BrdU and DCX positive cells in the hippocampus and subventricular zone. Results showed that treatment with LEO ameliorated the depression-like behavior induced by the chronic administration of corticosterone as observed in the LEO + Cort group. Cort treatment reduced the number of BrdU positive cells in the hippocampus and the subventricular zone. Treatment with LEO prevented the corticosterone-induced reduction in the number of BrdU positive cells (LEO + Cort group) demonstrating the neurogenic effect of LEO under high corticosterone conditions. Chronic administration of high dose of corticosterone significantly reduced the dendritic complexity of immature neurons. On the contrary, treatment with LEO increased dendritic complexity of immature neurons under high corticosterone conditions (LEO + Cort group). The improved neurogenesis and dendritic complexity observed in the LEO + Cort group demonstrated a clear restorative effect of LEO under high corticosterone conditions. However, 2-3 days after the treatment, the levels of BDNF were upregulated in the LEO and LEO + Cort groups. Furthermore, the concentration of oxytocin in serum, 2-3 days after the treatment, showed to be upregulated in the LEO group alone. The present study has provided evidence of the biological effect of LEO on neuroplasticity and neurogenesis. Also, this study contributes to the understanding of the mechanism of action of LEO in an animal model where depression- and anxiety-like behavior and reduced neurogenesis were induced by high corticosterone administration.

Barriers to Receiving HPV Vaccination Among Men in a Chinese Community: A Qualitative Study in Hong Kong.

Human papillomavirus (HPV) can cause various diseases; low-risk strains can cause genital warts, whereas high-risk strains can cause cervical cancer and cancer of the vulva in women and cancers of the penis, anus, and oropharynx in men. Although HPV affects men, literature has reported that the prevalence of HPV vaccination is far lower among men than among women. Few studies have examined perceptions and acceptability of the HPV vaccine among men, particularly in Chinese communities. In this study, the acceptability of the HPV vaccine to men was investigated using Hong Kong men as a case group. A qualitative research approach was adopted. Thirty-nine men were purposively sampled for the in-depth individual semistructured interviews from June to October 2017 to investigate their perceptions of the HPV vaccine and the barriers for them to receive the vaccination. Limited knowledge and awareness of HPV-related issues, low perceived risk of HPV infection, perceived association between HPV vaccine and promiscuity, and lack of accessible official information on HPV-related topics were identified as the key barriers. These barriers intermingled with the sociocultural environment, cultural values of sexuality, and patriarchal gender values. HPV vaccine is shown to be socially constructed as a vaccine for women exclusively and for promiscuity. The participants were discouraged from receiving HPV vaccination because of its signaling of socially deviant promiscuity. Cultural taboo on sex served as a social oppression of open discussion about HPV vaccine and affected the participants' perceived need of vaccination. Perceived insignificance of reproductive organs also influenced the participants' perceived need of vaccination.

The Role of Counterfactual Thinking in Narrative Persuasion: Its Impact on Patients' Adherence to Treatment Regimen.

The purpose of this study is twofold: (1) to explicate the underlying process of how narratives, accompanied with counterfactual thinking, exert cognitive and affective influence on audiences and (2) to examine how counterfactual thinking and regulatory focus, as story characteristics, enhance the persuasiveness of the narrative. Participants in the experiment were exposed to animated narratives in which the protagonist described her nonadherence to the peritoneal dialysis treatment regimen that resulted in her hospitalization. One hundred thirty-six patients undergoing peritoneal dialysis participated in a 2 (Goal failure framing: promotion-framed failure versus prevention-framed failure) by 2 (Counterfactual thinking: additive counterfactuals versus subtractive counterfactuals) between-subject factorial experiment. The analyses showed that narratives with additive counterfactuals, as opposed to those with subtractive counterfactuals, elicited greater anticipated regret and mental simulation, and, in turn, influenced the audience's attitude toward and intention of adherence. More important, promotion-/prevention-framed failure and additive/subtractive counterfactuals jointly influenced the audience's anticipated regret and mental simulation. Specifically, in the prevention-framed goal failure condition, narratives with additive counterfactuals elicited greater anticipated regret and mental simulation; however, in the promotion-framed goal failure condition, there was no significant difference on anticipated regret and mental simulation between narratives with subtractive counterfactuals and those with additive counterfactuals. The theoretical and practical implications were discussed.

Repeated Testing With the Hypertonic Saline Assay in Mice for Screening of Analgesic Activity.

BACKGROUND: In vivo animal assays are a cornerstone of preclinical pain research. An optimal stimulus for determining the activity of potential analgesics would produce responses of a consistent magnitude on repeated testing. Intraplantar (i.pl.) injection of hypertonic saline (HS) in mice produces robust nociceptive responses to different analgesics, without evidence of tissue damage. Here, we investigated whether the nociceptive response is changed by repeating the injection at different times and sites in a mouse and whether it is attenuated by morphine. METHODS: We conducted randomized and blinded experiments to assess responses to repeated i.pl. 10% HS in female CD-1 mice. An injection of HS was followed by a second injection into the same hind paw at 4 hours, 24 hours, or 7 days. A separate group of mice each received i.pl. injections at 5, 10, and 15 days. In 2 independent experiments, 30 minutes after initial HS injections in the ipsilateral hind paw, mice received HS injection into the contralateral hind paw or ipsilateral forepaw. The ability of morphine to block the nociceptive responses was examined by injecting morphine at 5-day intervals. RESULTS: Repeated injection of HS did not alter the responses at 4 hours (84 vs 75 seconds; mean difference [95% CI], -9 [-40 to 23]; P = .6), 24 hours (122 vs 113 seconds; -6 [-24 to 12]; P = .5), or 7 days (112 vs 113 seconds; -0.3 [-12 to 11]; P = .95) or at multiple injections (day 0, 122 seconds vs day 5, 121 seconds; -0.3 [-28 to 27], P > .99; day 10, 118 seconds; 2.5 [-36 to 41], P = .99; day 15, 119 seconds; 2 [-36 to 38], P = .99). A previous hind paw injection did not change the responses of the contralateral hind paw (right, 93 seconds versus left, 96 seconds; -3 [-20 to 13], P = .7) or of the ipsilateral forepaw (forepaw after HS, 146 seconds versus forepaw after 0.9% saline, 149 seconds; -3 [-28 to 22], P = .8). Morphine dose-dependently attenuated HS responses (control, 94 seconds vs 4 mg/kg, 66 seconds; 29 [-7 to 64], P = .12; vs 10 mg/kg, 27 seconds; 67 [44-90], P < .0001; 4 vs 10 mg/kg, 67 [44-90], P = .03). CONCLUSIONS: The repetition of i.pl. HS produces consistent reproducible responses without tissue damage. This results in efficient, rapid detection of analgesic activity, reducing the number of animals required.

Antinociception by intrathecal delivery of the novel non-opioid 1-amino-1-cyclobutanecarboxylic acid.

BACKGROUND: Neuraxial opioids are widely used for intraoperative and post-operative analgesia. The risk of severe adverse effects including respiratory depression accompanies this analgesia, prompting the need for effective non-opioid alternatives. Systemic 1-amino-1-cyclobutanecarboxylic acid showed promise in preliminary studies to produce antinociception without observable toxicity. However, the effects of 1-amino-1-cyclobutanecarboxylic acid after intrathecal administration are unknown. The aim of this study was to determine whether intrathecal administration of 1-amino-1-cyclobutanecarboxylic acid produces antinociceptive effects in murine models and to elucidate its site and receptor mechanism of action. METHODS: Female CD-1 mice were randomized to receive intrathecal, intraperitoneal and intraplantar injections of 1-amino-1-cyclobutanecarboxylic acid. Animals receiving intrathecal injections were anaesthetized and injected between L5 and L6. Animals then received an intraplantar injection of 10% hypertonic saline into the right hindpaw and were video-recorded for 30 min. Videos were analyzed by a blinded observer who determined the duration that animals exhibited nocifensive responses. RESULTS: Intrathecal or intraperitoneal administration of 1-amino-1-cyclobutanecarboxylic acid reduced the time that animals exhibited nocifensive behaviour, whereas intraplantar administration produced no effect. The effects of intrathecal 1-amino-1-cyclobutanecarboxylic acid were restricted in dermatomal distribution, reversible and produced little or no depression of respiratory rate. An NMDA antagonist blocked antinociception, while mu-opioid or GABAB antagonists did not prevent ACBC antinociception. CONCLUSIONS: Intrathecal 1-amino-1-cyclobutanecarboxylic acid in mice produces robust, brief antinociceptive effects with a dermatomal distribution corresponding to the lumbar site of administration. This amino acid merits further exploration as a non-opioid neuraxial analgesic with little or no respiratory side effects. SIGNIFICANCE: The novel, non-opioid analgesic, 1-amino-1-cyclobutanecarboxylic acid, produced robust, reversible and localized antinociception in murine models of pain. This study provides evidence supporting further investigation and development of 1-amino-1-cyclobutanecarboxylic acid as a non-opioid spinal analgesic.