Impacts of xylazine on fentanyl demand, body weight, and acute withdrawal in rats: A comparison to lofexidine.

The opioid use landscape has recently shifted to include xylazine, a veterinary anesthetic, as an adulterant in the fentanyl supply. The health impacts of xylazine as an emerging fentanyl adulterant has raised alarm regarding xylazine as a public health threat, warranting research on the impacts of xylazine on fentanyl's behavioral effects. No prior studies have evaluated the effects of xylazine on fentanyl consumption at various unit doses, fentanyl demand, or withdrawal as compared to the Food and Drug Administration-approved opioid withdrawal medication, lofexidine (Lucemyra®). This is important because lofexidine and xylazine are both adrenergic α2a (A2aR) agonists, however, lofexidine is not a noted fentanyl adulterant. Here we evaluated xylazine and lofexidine combined with self-administered fentanyl doses in male and female rats and evaluated fentanyl demand, body weight, and acute withdrawal. Consumption of fentanyl alone increased at various unit doses compared to saline. Xylazine but not lofexidine shifted fentanyl consumption downward at a number of unit doses, however, both lofexidine and xylazine suppressed fentanyl demand intensity as compared to a fentanyl alone control group. Further, both fentanyl + lofexidine and fentanyl + xylazine reduced behavioral signs of fentanyl withdrawal immediately following SA, but signs increased by 12 h only in the xylazine co-exposed group. Weight loss occurred throughout fentanyl SA and withdrawal regardless of group, although the xylazine group lost significantly more weight during the first 24 h of withdrawal than the other two groups. Severity of weight loss during the first 24 h of withdrawal was also correlated with severity of somatic signs of fentanyl withdrawal. Together, these results suggest that body weight loss may be an important indicator of withdrawal severity during acute withdrawal from the xylazine/fentanyl combination, warranting further translational evaluation.

Xylazine: The Drug Taking the World By Storm: What You Need to Know.

Xylazine has taken the world by storm and proactive strategies are urgently needed to combat its negative impacts on population health. Xylazine is an unscheduled non-opioid indicated as a veterinary tranquilizer, also known as "Tranq." This drug is commonly used in combination with other drugs, such as heroin, fentanyl, and cocaine. Xylazine can be used orally, intranasally, sniffed, smoked, and injected, but is mostly used intravenously. Adverse effects of xylazine are secondary to central nervous system (CNS), cardiovascular, and respiratory function depression. When alpha-2-receptors in the cardiovascular and respiratory systems are stimulated, physiological effects include bradycardia, hypotension, and respiratory and CNS depression. There are currently no U.S. Food and Drug Administration-approved medications for the treatment of xylazine withdrawal or reversal of its overdose. Therefore, it is imperative that health care providers are trained to recognize these signs and symptoms and intervene proactively. [Journal of Psychosocial Nursing and Mental Health Services, 61(12), 7-10.].

Xylazine Adulteration of the Heroin-Fentanyl Drug Supply : A Narrative Review.

Xylazine is an animal sedative, approved by the U.S. Food and Drug Administration, that is commonly used in veterinary medicine and is not approved for human use. Since 2016, xylazine has consistently appeared in the illicitly manufactured fentanyl supply and has significantly increased in prevalence, likely due to its low cost, easy availability, and presumed synergistic psychoactive effect. Clinical experience along with the available pertinent research were used to review xylazine adulteration of the drug supply and provide guidance on the care of patients exposed to xylazine. This review discusses xylazine pharmacology, animal and human clinical effects, and what is known to date about care of patients experiencing acute overdose, xylazine-fentanyl withdrawal, and xylazine-associated wounds.

Reducing the harms of xylazine: clinical approaches, research deficits, and public health context.

OBJECTIVES: Xylazine has emerged as a consistent part of the unregulated drug supply in recent months. We discuss major domains of xylazine's harm, current knowledge deficits, clinical and harm reduction strategies for minimizing harm, and xylazine's public health and policy context. As an interdisciplinary team from across the USA, we have pooled our knowledge to provide an overview of xylazine's current and emerging contexts. METHODS: To inform this essay, the pertinent literature was reviewed, clinical knowledge and protocols were shared by multiple clinicians with direct expertise, and policy and public health context were added by expert authors. RESULTS: We describe xylazine's major harm domains-acute poisoning, extended sedation, and wounds, along with anemia and hyperglycemia, which have been reported anecdotally but lack as clear of a connection to xylazine. Current successful practices for xylazine wound care are detailed. Understanding xylazine's epidemiology will also require greater investment in drug checking and surveillance. Finally, approaches to community-based wound care are discussed, along with an orientation to the larger policy and public health context. CONCLUSIONS: Addressing the harms of xylazine requires interdisciplinary participation, investment in community-based harm reduction strategies, and improved drug supply surveillance. The relatively unique context of xylazine demands buy-in from public health professionals, harm reduction professionals, clinicians, basic science researchers, policymakers and more.

Comprehensive testing and rapid dissemination of local drug supply surveillance data in Rhode Island.

BACKGROUND: The North American overdose crisis has continued at unprecedented rates with more than 100,000 overdose deaths estimated to have occurred in the United States in 2022. Regional variations in overdose rates signify differences in local drug supplies. State-level drug supply surveillance systems have been limited in their ability to document and communicate the rapidly changing drug supplies which can hinder harm reduction efforts at the community level. We sought to address by piloting a two-year, community-engaged local drug supply surveillance program in Rhode Island (RI). METHODS: The first set of samples (n = 125) were collected from May 2022 to January 2023 across RI and included used paraphernalia (e.g., cookers), refuse (e.g., baggies), and product. Samples were tested using comprehensive toxicology testing approaches via liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Results were disseminated to participants and the broader public across platforms. RESULTS: Fentanyl was detected in 67.2% of all samples tested. 39.2% (n = 49) of samples were expected to be fentanyl. Xylazine was detected in 41.6% of all samples-always in combination with fentanyl-and no samples were expected to contain xylazine. In expected stimulant samples (n = 39), 10% contained fentanyl and/or analogues as major substances and 30.8% contained trace amounts of fentanyl and/or analogues. In expected stimulant samples, 15.4% contained xylazine with fentanyl. No opioids or benzodiazepines were detected in expected hallucinogen or dissociative samples (n = 7). In expected benzodiazepine samples (n = 8), no opioids were detected. CONCLUSIONS: Our results describe part of the local drug supply in Rhode Island, including a presence of NPS and adulterants (e.g., designer benzodiazepines, xylazine). Importantly, our findings underscore the feasibility of developing a community-driven drug supply surveillance database. Expanding drug supply surveillance initiatives is imperative for improving the health and safety of people who use drugs and informing public health approaches to addressing the overdose crisis.

Harm reduction and emergency medical services: Opportunities for evidence-based programming.

Overdose fatalities are increasingly attributed to synthetic opioids, including fentanyl, which may be added to samples of illicit substances unknowingly to the user. As recently as April 2023, the Centers for Disease Control and Prevention has also raised awareness of the risks of xylazine, an animal tranquilizer that has been found in adulterated samples of illicit substance. A growing body of evidence supports the use of drug testing services, including fentanyl and xylazine test strips, to reduce the risks associated with substance use and prevent fatal overdoses. Emergency medical services clinicians serve on the frontline of the opioid epidemic and are uniquely positioned to distribute harm reduction materials. In this article, we advocate for emergency medical services to distribute fentanyl and xylazine test strips. We also critically evaluate legal and other barriers to implementation.

Xylazine-involved fatal overdoses and localized geographic clustering: Cook County, IL, 2019-2022.

BACKGROUND: Xylazine, a veterinary analgesic sedative, is circulating in the illicit drug markets of at least 23 states including Illinois. We conducted a geographic analysis to better identify the spatial distribution of xylazine-involved fatal overdoses in Cook County, IL. METHODS: Cook County Medical Examiner Office's (CCMEO) publicly available data was used to identify xylazine-involved fatal overdoses from January 1, 2019, to June 30, 2022. Xylazine-positive (cases) to xylazine-negative groups with drug mixtures involving fentanyl, alcohol and stimulants (controls) were matched on age, race, sex, and year of death. Ripley's K-function was used to examine the likelihood of case clustering compared to controls with the Bernoulli spatial scan deployed to identify specific geographic clusters. RESULTS: Almost all (94.4%) xylazine-positive overdoses contained fentanyl. Using coordinate-based matching, we found that approximately 3% of xylazine overdose incidents were co-located with other overdoses. Xylazine cases clustered to from 0 to 16.1 miles (max=10.6 miles). Results of the Bernoulli spatial scan varied by control group with two high-risk clusters found relative to alcohol and stimulants and a low-risk cluster relative to fentanyl. Differences in co-occurring drugs were found between xylazine and fentanyl groups like the absolute number of drugs (4.6v 3.4, p<0.0001) and fentanyl analog types. CONCLUSIONS: Xylazine fatal overdose incident locations exhibited localized clustering relative to fentanyl overdoses but clusters were not precisely detected at these scales. Even so, our results, especially relative to repeat overdose micro "hot spots", offer insight on targeting harm reduction and other services at the neighborhood-level.

Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report.

BACKGROUND: Xylazine is an alpha-2 adrenergic agonist commonly used as a large animal anesthetic. It is used as an adulterant in illicit opioids, and it is now well established that its synergistic effect with opioids increases lethality. The amount of xylazine adulterating illicit opioids is growing at an alarming rate, present in almost one-third of opioid overdose deaths reported in Philadelphia in 2019. Despite this, there are no reports considering the management of patients using xylazine chronically. In particular, there are no reported cases detailing the management of xylazine withdrawal or exploring the potential for ongoing treatment for those in recovery from xylazine use. CASE SUMMARY: We present the case of a 29 year old female with opioid use disorder and chronic xylazine use, admitted to the intensive care unit for treatment of chronic lower extremity wounds thought to be due to xylazine injection. Her xylazine withdrawal was managed with a combination of dexmedetomidine infusion, phenobarbital and tizanidine, later transitioned to clonidine. By hospital day 4 she was no longer experiencing withdrawal symptoms. She was transitioned from full-agonist opioids for pain to buprenorphine via a buprenorphine "micro-induction" and was ultimately discharged on buprenorphine, clonidine, and gabapentin on day 19 of admission. CLINICAL SIGNIFICANCE: This case illustrates a potential treatment pathway that allows for safe and comfortable xylazine withdrawal in hospitalized patients. It also provides an introduction into several medical concerns affecting this patient population specifically, including xylazine-mediated soft tissue wounds.

The Influence of Xylazine and Clonidine on Lung Ultrasound-Induced Pulmonary Capillary Hemorrhage in Spontaneously Hypertensive Rats.

Induction of pulmonary capillary hemorrhage (PCH) by lung ultrasound (LUS) depends not only on physical exposure parameters but also on physiologic conditions and drug treatment. We studied the influence of xylazine and clonidine on LUS-induced PCH in spontaneously hypertensive and normotensive rats using diagnostic B-mode ultrasound at 7.3 MHz. Using ketamine anesthesia, rats receiving saline, xylazine, or clonidine treatment were tested with different pulse peak rarefactional pressure amplitudes in 5 min exposures. Results with xylazine or clonidine in spontaneously hypertensive rats were not significantly different at the three exposure pulse peak rarefactional pressure amplitudes, and thresholds were lower (2.2 MPa) than with saline (2.6 MPa). Variations in LUS PCH were not correlated with mean systemic blood pressure. Similar to previous findings for dexmedetomidine, the clinical drug clonidine tended to increase susceptibility to LUS PCH.

Ketamine and xylazine effects in murine model of acute pancreatitis.

Ketamine and xylazine (Ket/Xyl) are anesthetic agents that target neural pathways and are commonly used in combination in mouse studies. Since neural pathways can modulate acute pancreatitis severity, we asked if Ket/Xyl affect disease severity. C57BL/6 mice were treated with six hourly injections of cerulein to induce mild acute pancreatitis. Mice were also treated with and without ketamine, xylazine, and Ket/Xyl before pancreatitis induction in vivo and in vitro. Ket/Xyl pretreatment in vivo increased selected parameters of pancreatitis severity such as trypsin activity and edema; these effects were predominantly mediated by xylazine. Ket/Xyl also changed markers of autophagy. These in vivo effects of Ket/Xyl were not attenuated by atropine. The drugs had no little to no effect on pancreatitis responses in isolated pancreatic cells or lobules. These findings suggest that Ket/Xyl administration can have substantial effect on acute pancreatitis outcomes through nonmuscarinic neural pathways. Given widespread use of this anesthetic combination in experimental animal models, future studies of inflammation and injury using Ket/Xyl should be interpreted with caution.NEW & NOTEWORTHY Ketamine and xylazine anesthetic agent administration before acute pancreatitis induction in mice lead to changes in pancreatitis responses independent of acute pancreatitis induction. Future studies should consider the potential effects of anesthesia administration when studying disease processes associated with inflammation and injury.

Effect of xylazine administration before laparoscopic abomasopexy to correct left displaced abomasum on markers of stress in dairy cows.

Left displacement of the abomasum in dairy cows is a disease diagnosed all over the world. In Germany, a common method for its correction is laparoscopic abomasopexy (LA). The aim of the study was to assess cortisol and substance P concentrations, behavioral patterns, and feeding and rumination times during and after LA in cattle treated with xylazine before LA compared with nonsedated cattle. A total of 28 cattle that had been referred to a veterinary teaching hospital with a diagnosis of left displacement of the abomasum were randomly assigned to 1 of 2 groups. Surgery was performed according to a standardized protocol. Animals of XYL (n = 14) received xylazine (0.02 mg/kg body weight i.v.) before surgery, and animals of CON (n = 14) received a placebo (0.9% saline i.v.). All cows received ketoprofen (3 mg/kg body weight i.v.) twice, and benzyl penicillin procaine (20,000 IU/kg body weight i.m.) for 5 ± 1 d. Blood samples for the determination of plasma cortisol concentration (PCC) and plasma substance P concentration were taken 3 h before surgery (+00:00), at 1100 h (+03:00), 1115 h (+03:15, skin incision), 1130 h (+03:30), 1145 h (+03:45, dorsal recumbency), 1200 h (+04:00, end of surgery), 1230 h (+04:30), 1300 h (+05:00), 1400 h (+06:00), and 1100 h (+27:00) the following day. Behavior was assessed on the day of surgery and the following day (0800, 1300, and 1700 h), and during surgery. Feeding and rumination time were recorded for 24 h after surgery. Data analysis was done using R (R Foundation for Statistical Computing, Vienna, Austria). The LA was performed in all animals without negative effects. The PCC was lower in XYL than in CON at all times and significantly lower at +03:30. In CON, PCC was significantly higher at +03:45, +04:00, and +04:30 compared with +03:00. In XYL, PCC was significantly lower at +03:15 and +03:30 compared with +03:00, and significantly higher at +04:00 and +04:30. Plasma substance P concentration did not differ between groups. No differences were observed in behavior between CON and XYL. Feeding and rumination times did not differ between groups. Animals in XYL showed significantly more chews per bolus after surgery than animals in CON. In conclusion, administration of xylazine before LA results in lower stress levels for cattle during the course of LA, especially before being put into lateral and dorsal recumbency. Therefore, in the opinion of the authors, xylazine administration can be recommended before LA to improve the well-being of the animals during and after surgery.

Protocols using detomidine and oxytocin induce ex copula ejaculation in stallions.

Tricyclic antidepressives, such as imipramine, indirectly induce ejaculation by increasing the noradrenaline concentration, which triggers an α-adrenergic response, whereas α-adrenergic agonists, such as xylazine and detomidine, directly trigger ejaculation by activating the α-1 adrenergic receptors. Furthermore, serum oxytocin concentrations in stallions increase drastically before ejaculation, but decline immediately thereafter, implicating the role of this hormone in emission. The objectives of the present study were to: 1) compare the efficiency of various protocols for inducing ex copula ejaculation in stallions, 2) evaluate the benefits of including oxytocin in the protocols, and 3) compare the semen characteristics of ex copula versus in copula ejaculates. Nine protocols were used to induce ex copula ejaculation using various combinations of xylazine (X; 0.66 mg/kg, iv); oxytocin (O; 20 IU, iv), imipramine (I; 3 mg/kg, orally), and detomidine (D; 0.02 mg/kg, iv). Imipramine was given 2 h prior to the administration of α-adrenergic agonist (detomidine or xylazine) and oxytocin. If ejaculation did not occur within 10 min after treatment with an α-adrenergic agonist, a half-dose of the same product was injected. Twelve sexually mature stallions (6-26 y) were used; 9 of 12 stallions responded to the treatment. Two stallions responded to X or XO, four stallions responded to IX and IXO, one stallion responded to DO, and five responded to IDO. Stallions that responded to detomidine did not respond to xylazine. No stallion ejaculated in response to D, ID, or IO. Erections and masturbation occurred only in imipramine-treated stallions. Sperm quality was similar among all the protocols and was not significantly different from those in in copula ejaculates collected with an artificial vagina. In a separate trial, none of these protocols induced ex copula ejaculation in 2-3 y old stallions. The side effects included sialorrhea after imipramine administration in all the stallions and sedation after administration of xylazine or detomidine. In conclusion, the new protocol, IDO, and the traditional protocol, IX, had similar results, with IDO being a useful alternative protocol in stallions for which IX was not effective. Therefore, attempts using both the protocols are encouraged, as stallions that ejaculated upon administration of detomidine did not ejaculate when xylazine was administered, whereas those that responded to xylazine did not respond to detomidine.

Evaluation of the effects of commonly used α2-adrenergic receptor agonists alone and in combination with butorphanol tartrate on objective measurements of lameness in horses.

OBJECTIVE: To determine the effects of 3 α2-adrenergic receptor agonists (α2-ARAs), alone or in combination with butorphanol tartrate, on objective measurements of lameness in horses. ANIMALS: 17 adult polo horses with naturally occurring forelimb or hind limb lameness (or both). PROCEDURES: In a crossover design, each horse received each protocol (saline [0.09% NaCl] solution [2 mL, IV] or xylazine hydrochloride [0.33 mg/kg, IV], detomidine hydrochloride [0.007 mg/kg, IV], or romifidine hydrochloride [0.033 mg/kg, IV] alone or in combination with butorphanol [0.007 mg/kg, IV]) in random order, with a washout period (≥ 7 days) between protocols. Horses were assessed immediately prior to (baseline) and 10, 15, 20, 30, and 40 minutes after administration of each protocol for degree of sedation, mechanical nociceptive threshold (MNT), and objective lameness measurements. RESULTS: Compared with baseline values, sedation scores and MNTs were significantly higher at all evaluated time points following administration of all sedation protocols except xylazine alone; following administration of xylazine alone, sedation scores and MNTs were significantly higher at ≤ 30 minutes and ≤ 20 minutes, respectively. Significant differences in objective forelimb lameness measurements were noted after administration of the 3 α2-ARA-butorphanol combinations. Most significant differences in objective measurements of hind limb lameness were detected after administration of detomidine or romifidine, alone or in combination with butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE: In the study horses, xylazine alone had the least impact on objective lameness measurements. The administration of α2-ARAs, particularly detomidine or romifidine, alone or in combination with butorphanol, resulted in small but significant effects on objective lameness measurements.

Investigation of the Effects of Spinal Dexamethasone Injection as a Premedication in Rabbit Anesthesia.

Anesthesia and analgesia are important in human and veterinary medicine, especially in surgical procedures. Rodents, avians, and exotic species are required to be anesthetized using an appropriate anesthetic regimen. This study aimed to suggest a new anesthetic drug and method in order to facilitate anesthesia as well as analgesia among rabbits, laboratory animals, and humans. Spinal injection of dexamethasone combined with intramuscular ketamine among rabbits can play the role of premedication agents. A total of 24 healthy white adult rabbits from New-Zealand were equally assigned into four groups. Groups 1, 2, 3, and 4 were subjected to spinal xylazine (5mg/kg) with ketamine (35mg/kg,IM), spinal dexamethasone (0.37mg/kg-four times diluted) with ketamine (35mg/kg,IM), dexamethasone (4mg/kg,IM) with ketamine (35mg/kg,IM), and spinal dexamethasone (0.37mg/kg-four times diluted), respectively. The results showed that there was a significant difference in terms of clinical reflexes recorded for group 2, compared to groups 1 and 3. A significant difference was also observed regarding clinical reflexes between group 2 and the other groups. Furthermore, no abnormality was observed in terms of histological sections within groups 2 and 4. Spinal dexamethasone can be used as a premedication combined with ketamine in rabbit anesthesia.

Guaiphenesin-ketamine-xylazine infusion to maintain anesthesia in mules undergoing field castration.

BACKGROUND: In order to determine whether a combination of guaiphenesin, ketamine and xylazine can induce safe and satisfactory anaesthesia in mules undergoing field castration, eight healthy adult intact male mules were employed. They were premedicated with intravenous (IV) xylazine (1.3 mg/kg); an additional dose of xylazine (0.3 mg/kg IV) was administered in case of inadequate depth of sedation. Anaesthesia was induced with IV thiopental (6 mg/kg). The quality of sedation and induction was recorded. Anaesthesia was maintained with an infusion of guaiphenesin (50 mg/mL), ketamine (2 mg/mL) and xylazine (1 mg/mL) (GKX). The spermatic cord of each testis was infiltrated with 5 mL of 2% lidocaine. During anaesthesia heart rate (HR), respiratory rate (RR), rectal temperature (RT) and haemoglobin oxygen saturation (SpO2) were measured every 5 min. The data were analysed with simple one-way analysis of variance (ANOVA). A P value < 0.05 was considered statistically significant. Time of anesthesia, time of surgery and time of recovery were recorded. RESULTS: Only one mule required an additional dose of xylazine to achieve a satisfactory depth of sedation. Thiopental at the dose of 6 mg/kg IV resulted in smooth induction and lateral recumbency in all animals. GKX provided adequate anaesthesia to perform castration in all mules. Muscle relaxation was deemed adequate and physiological variables remained stable and within references values during the anaesthesia and did not change in response to surgical stimulation. Time (mean ± standard deviation) from the end of the infusion to sternal recumbency and time from sternal recumbency to standing were 27.7 ± 4.6 and 30.1 ± 7.7 min, respectively. CONCLUSIONS: The combination of xylazine, thiopental and GKX provides satisfactory short-term anaesthesia in mules undergoing field castration.

Retrospective evaluation of the effectiveness of xylazine for inducing emesis in cats: 48 cats (2011-2015).

OBJECTIVE: To determine the effectiveness of xylazine for the induction of emesis in cats that were suspected of ingesting potentially toxic substances or foreign objects. DESIGN: Retrospective study. SETTING: Private emergency and specialty referral hospital. ANIMALS: Forty-eight client-owned cats that were administered xylazine to induce emesis for decontamination of a toxic substance or expulsion of an ingested foreign object. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The medical records of 48 cats presenting for known or suspected ingestion of foreign material that underwent decontamination with xylazine were reviewed. Signalment, material ingested, dose and route of xylazine administration, success of emesis and recovery of foreign material ingested, use of a reversal agent, and adverse effects were noted. The induction of emesis was successful in 29/48 (60%) of cats. Sedation was the most common adverse effect and was noted in 15/48 (31%) of patients. CONCLUSIONS: Xylazine is safe and reasonably effective at inducing emesis in cats.

Retroauricular Approach for Targeted Cochlear Therapy Experiments in Wistar Albino Rats.

BACKGROUND: As the idea of stem cell technology in the treatment of sensorial hearing loss has emerged over the past decades, the need for in vivo models for related experiments has become explicit. One of the most common experimental models for inner ear stem cell delivery experiments is the Wistar albino rat. AIMS: To investigate the surgical anatomy of the temporal bone of the Wistar albino rat with respect to the dissection steps, operative techniques and potential pitfalls of surgery. STUDY DESIGN: Animal experimentation. METHODS: Adult Wistar albino rats were operated on via the retroauricular approach under an operation microscope. The anatomy of the temporal bone, the surgical route to the temporal bulla and the inner ear were investigated. Technical details of surgical steps, complications and potential pitfalls during the surgery were noted. RESULTS: The study group consisted of 40 adult Wistar albino rats. The mean times to reach the bulla and to achieve cochleostomy were 4.3 (2-13 min) and 7.5 min (3.5-22 min), respectively. The mean width of the facial nerve was 0.84 mm (0.42-1.25 mm). The stapedial artery lay nearly perpendicular to the course of the facial nerve (88-93 °C). There were three major complications: two large cochleostomies and one massive bleed from the stapedial artery. CONCLUSION: The facial nerve was the key anatomical landmark in locating the bulla. By retrograde tracing of the facial nerve, it was possible to find the bulla ventral (inferior) to the main trunk. The facial nerve trunk was the upper limit when drilling the bulla. By dissecting the main trunk of the facial nerve and retracting cranially, a large drilling space could be achieved. Our results suggest that the retroauricular approach is an effective, feasible route for inner ear drug delivery experiments in Wistar albino rats.

Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function.

Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100µg/kg/side) and H-89(10µM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders.

The effect of different combinations of local anaesthesia, sedative and non-steroidal anti-inflammatory drugs on daily growth rates of dairy calves after disbudding.

AIM: To assess the effect of sedation and local anaesthesia (LA) at disbudding, and the addition of meloxicam or ketoprofen treatment, on weight gain in dairy calves following disbudding. METHODS: Friesian-Jersey cross calves, from four dairy farms, were enrolled when 3-6 weeks old. All calves (n=271) were disbudded by veterinary personnel and randomly assigned to six groups: 136 were disbudded without sedation or LA, of which 31 received 20 mg meloxicam S/C and 75 received 150 mg ketoprofen I/M. A further 135 were disbudded with sedation (0.25 mg/kg xylazine I/M) and LA, of which 30 also received meloxicam and 75 received ketoprofen. Calves were weighed 3 days before, and 15 and 30 days after, disbudding (Day 0). Daily weight gain was analysed using mixed models and ANOVA. RESULTS: Complete results were obtained from 263 calves. From Day -3 to Day 15, the growth rate of calves disbudded without pain relief (0.53 (95% CI=0.47-0.60) kg/day) was less that of calves disbudded with some form of pain relief (0.65 (95% CI=0.62-0.68) kg/d; p=0.004). There was no difference between the effect of meloxicam or ketoprofen (p=1.00). An interaction between use of sedation and LA and additional non-steroidal anti-inflammatory drugs (NSAID) meant that NSAID treatment did not increase growth rates in calves disbudded with sedation and LA but did increase growth rates for calves disbudded without pain relief (p<0.05). From Day 16 to Day 30 there was no effect of NSAID treatment on growth rate, but calves receiving LA and sedation grew faster (0.74 (95% CI=0.69-0.80) kg/day) than calves disbudded without LA and sedation (0.66 (95% CI=0.61-0.71) kg/day; p=0.018). From Day -3 to Day 30, calves disbudded with sedation and LA grew faster (0.71 (95%CI=0.64-0.77) kg/day) than calves disbudded without sedation and LA (0.60 (95% CI=0.55-0.65) kg/day; p=0.011). However, addition of NSAID to sedation and LA made no further difference to growth rates (p=0.69). CONCLUSIONS: Dairy calves disbudded with no pain relief had slower growth rates than calves receiving pain relief. From Day 15 to 30 calves given no pain relief, or NSAID alone, grew more slowly than those receiving sedation and LA at disbudding. The addition of NSAID treatment to sedation and LA did not further increase growth rates. CLINICAL RELEVANCE: This study adds to the evidence that pain management when disbudding is beneficial for calf productivity as well as calf welfare.