EFFECTS OF MU OPIOID RECEPTOR AGONISTS ON INTRACRANIAL SELF-STIMULATION IN THE ABSENCE AND PRESENCE OF “PAIN” IN RATS

Pain is a significant health problem. Mu opioid receptor agonists are used clinically as analgesics, but their use is constrained by high abuse liability. Intracranial self-stimulation (ICSS) is a preclinical behavioral procedure that has been used to assess abuse potential of opioids, and drug-induced facilitation of ICSS is interpreted as an abuse-related effect. ICSS can also be used as a behavioral baseline to detect affective dimensions of pain. Specifically, pain-related depression of ICSS can model pain-related depression of behavior and mood, and drug-induced blockade of pain-related ICSS depression can serve as a measure of affective analgesia. This dissertation used mu agonists that vary in efficacy at the mu receptor (methadone\u3e fentanyl\u3e morphine\u3e hydrocodone\u3e buprenorphine\u3e nalbuphine) and compared their effects on ICSS in the absence (phase one) or presence (phase 2) of pain. Adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for brain stimulation. Different frequencies of stimulation maintained a frequency-dependent increase in ICSS rates, and permitted detection of both rate-increasing and rate-decreasing treatment effects. During phase 1, medium- and high-efficacy mu agonists produced initial rate-decreasing effects, followed by abuse-related rate-increasing effects at later time points. Repeated morphine administration produced tolerance to its own rate-decreasing effects, cross-tolerance to rate-decreasing effects of other mu agonists, and enhanced expression of rate-increasing effects. Low efficacy mu agonists only produced rate-increasing effects, which were enhanced after repeated morphine. These results suggest that previous opioid exposure increases expression of abuse-related facilitation of ICSS by mu agonists regardless of efficacy. During phase 2, intraperitoneal administration of lactic acid (1.8%) served as a noxious stimulus to depress ICSS. All mu agonists blocked acid-induced depression of ICSS at doses similar to those that facilitated ICSS in the absence of pain. A higher intensity noxious stimulus (5.6 % acid) produced further depression of ICSS and reduced the antinociceptive potency of both methadone and nalbuphine. Morphine antinociception was resistant to tolerance in the assay of acid-depressed ICSS. Overall, these results provide a basis for comparing determinants of abuse-related opioid effects in the absence of pain with their affective analgesic effects in the presence of pain

New Strategic Deployment of Augmented and Virtual Reality for Enhancing Purchase Intentions and Brand Attitudes

 This study examines how Augmented Reality (AR) and Virtual Reality (VR) influence consumer decision-making in experiential retail. Through three experiments and qualitative feedback, AR proved more effective in driving purchase intentions by emphasizing product-focused mental imagery, while VR significantly enhanced brand attitudes through context-focused immersion. Results further indicated that presenting AR before VR yielded stronger outcomes, as AR’s product clarity primed consumers for the immersive brand narrative of VR. Qualitative insights underscored the emotional resonance and detailed visualization each technology provides, highlighting their complementary roles in shaping consumer perceptions. Employing a mixed methods approach, the research integrated statistical analyses of mental imagery, purchase intentions, and brand attitudes with participant narratives. While limitations include convenience sampling, controlled settings, and self-report measures, the findings offer a solid foundation for strategic AR-VR deployment. Future research should explore diverse contexts, user demographics, and long-term effects to deepen understanding of these emerging technologies

Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat

Background: Olvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound. Olvanil has potent anti-hyperalgesic effects in several experimental models of chronic pain. Here we report the inhibitory effects of olvanil on nociceptive processing using cultured dorsal root ganglion (DRG) neurons and compare the effects of capsaicin and olvanil on thermal nociceptive processing in vivo; potential contributions of the cannabinoid CB1 receptor to olvanil’s anti-hyperalgesic effects were also investigated.Methods: A hot plate analgesia meter was used to evaluate the anti-nociceptive effects of olvanil on capsaicin-induced thermal hyperalgesia and the role played by CB1 receptors in mediating these effects. Single cell calcium imaging studies of DRG neurons were employed to determine the desensitizing effects of olvanil on capsaicin-evoked calcium responses. Statistical analysis used Student’s t test or one way ANOVA followed by Dunnett’s post-hoctest as appropriate.Results: Both olvanil (100 nM) and capsaicin (100 nM) produced significant increases in intracellular calcium concentrations [Ca2+]I in cultured DRG neurons. Olvanil was able to des ensitise TRPV1 responses to further capsaicin exposure more effectively than capsaicin. Intra plantar injection of capsaicin (0.1, 0.3 and 1μg) produced a robust TRPV1-dependant thermal hyperalgesia in rats, whilst olvanil (0.1, 0.3 and 1μg) produced no hyperalgesia, emphasizing its lack of pungency. The highest dose of olvanil significantly reduced the hyperalgesic effects of capsaicin in vivo. Intraplantar injection of the selective cannabinoid CB1 receptor antagonist rimonabant (1μg) altered neither capsaicin-induced thermal hyperalgesia nor the desensitizing properties of olvanil, indicating a lack of involvement of CB1receptors.Conclusions: Olvanil is effective in reducing capsaicin-induced thermal hyperalgesia, probably via directly desensitizingTRPV1 channels in a CB 1 receptor-independent fashion. The results presented clearly support the potential for olvanil in the development of new topical analgesic preparations for treating chronic pain conditions while avoiding the unwanted side effects of capsaicin treatments

Comparison of Antidepressant‐Like and Abuse‐Related Effects of Phencyclidine in Rats

Preclinical Research N ‐methyl‐D‐aspartate ( NMDA ) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but abuse potential of these agents is a concern. The NMDA antagonist phencyclidine has known abuse liability but undefined efficacy as an antidepressant. To further evaluate the relationship between antidepressant‐like and abuse‐related effects of NMDA antagonists, this study evaluated the effects of phencyclidine (1.0–10.0 mg/kg) in male S prague‐ D awley rats responding under two procedures that have been used to assess antidepressant‐like effects (differential‐reinforcement‐of‐low‐rate [ DRL ] 72 s schedule of food reinforcement; n  = 9) and abuse‐related drug effects (intracranial self‐stimulation [ ICSS ]; n  = 6). Under the DRL 72 s schedule, phencyclidine (10.0 mg/kg) increased reinforcers and decreased responses without shifting the peak location of the interresponse time ( IRT ) distribution. Ketamine (10.0 mg/kg) also increased reinforcers and decreased responses, but unlike phencyclidine, it produced a rightward shift in the peak location of the IRT distribution. The 10.0 mg/kg phencyclidine dose that decreased DRL 72 s responding also decreased rates of ICSS for 50 min after its administration; however, abuse‐related ICSS facilitation was observed at later times (100–300 min) or after a lower phencyclidine dose (3.2 mg/kg). These results suggest that phencyclidine produces weaker antidepressant‐like effects, but stronger abuse‐related effects than ketamine in these procedures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109848/1/ddr21228.pd

Effects of the noncompetitive N‐methyl‐d‐aspartate receptor antagonists ketamine and MK‐801 on pain‐stimulated and pain‐depressed behaviour in rats

BackgroundPain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N‐methyl‐d‐aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing.MethodsThis study compared effects of the NMDA receptor antagonists ketamine and MK‐801 in assays of pain‐stimulated and pain‐depressed behaviour in rats. The nonsteroidal anti‐inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self‐stimulation (ICSS) in male Sprague–Dawley rats.ResultsKetamine (1.0–10.0 mg/kg) blocked acid‐stimulated stretching but failed to block acid‐induced depression of ICSS, whereas MK‐801 (0.01–0.1 mg/kg) blocked both acid‐stimulated stretching and acid‐induced depression of ICSS. These doses of ketamine and MK‐801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK‐801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid‐induced stimulation of stretching and depression of ICSS without altering control ICSS.ConclusionThese results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain‐depressed behaviours.What does this study addNMDA receptor antagonists produce dissociable effects on pain‐depressed behaviour.Provides evidence that pain‐depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134264/1/ejp847_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134264/2/ejp847.pd

In vivo effects of μ‐opioid receptor agonist/δ‐opioid receptor antagonist peptidomimetics following acute and repeated administration

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144260/1/bph14148.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144260/2/bph14148_am.pd

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

A study of surgical complications of ovariohysterectomy and pyometra in the bitch and cat

The literature on surgical complications of ovariohysterectomy and pyometra in the dog and cat is reviewed by considering first the aetiopathogenesis of pyometra, its diagnosis and different types of treatment, followed by the immediate and delayed complications which may develop during and after surgery. The role of suture materials in post-operative complications is also reviewed. The causes of death in pyometra cases admitted to Glasgow University Veterinary Hospital during the last eight years were studied. Use of laboratory tests aids the recognition of the mast suitable treatment for pyometra cases before and after the operation. Fluid therapy was used when necessary to improve renal function and to correct hypovolsmia. Dextrose saline was administered in 4 cases and Lactated Ringer's in another 4, One case needed whole blood transfusion (500 ml). Radiography was used in all the cases of pyometra both to confirm the diagnosis and to assess the degree of uterine enlargement. In 12 cases the uterus was grossly enlarged and this was easily detected on radiography. In 8 other cases the uterus was only slightly enlarged at laparotomy, but it was not detected as enlarged on radiography. Cultural examinations were carried out on the uterine content of 19 dogs and 1 cat which underwent ovariohysterectomy for pyometra. The examinations revealed a pure culture of E. coli in 12 dogs, a mixed growth of E, coli and 5, aureus in 1 and a mixture of E. coli and B-haemolytic, group G streptococci from another. No bacterial growth was found in 5 dogs. Bacteriology of the abdominal cavity during pyometra operation was evaluated in 19 dogs and 1 cat by examination of bacterial swabs which were taken from the abdominal cavity before and after removal of the uterus, from the uterine stump and both ovarian pedicles. Bacterial growth was found only in 3 cases where a mixture of anaerobic bacteria, Haemophilus canis and E. coli was isolated from the uterine stump. No bacterial growth was found from the other swabs. A pure culture of E, coli was isolated from the uterine content of one cat. In the majority of pyometra cases wound problems were the most common complications. In dogs with pyometra, care should be taken to correct fluid and electrolyte loss in dehydrated cases, and in animals with a high blood urea;, surgery is not recommended until it returns to normal. Post-operative care is important following pyometra surgery; the animal should be kept warm and fluid therapy such as dextrose saline, plasma, or blood transfusion in anaemic cases should be given if necessary. The routine ovariohysterectomy operation is contra-indicated in. bitches in oestrus. Chromic catgut suture material should be used fbr ovarian pedicle and uterine body ligatures. Care should be taken in ligating the ovarian and uterine vessels to prevent haemorrhage