Characterization and validation of a spontaneous acute and protracted oxycodone withdrawal model in male and female mice.

Opioid use disorder (OUD) is a serious health problem that may lead to physical dependence, in addition to affective disorders. Preclinical models are essential for studying the neurobiology of and developing pharmacotherapies to treat these problems. Historically, chronic morphine injections have most often been used to produce opioid-dependent animals, and withdrawal signs indicative of dependence were precipitated by administering an opioid antagonist. In the present studies, we have developed and validated a model of dependence on oxycodone (a widely prescribed opioid) during spontaneous withdrawal in male and female C57BL/6J mice. Dependence was induced by chronically administering oxycodone through osmotic minipumps at different doses for 7 days. Somatic withdrawal signs were measured after 3, 6, 24, and 48 h following minipump removal. Additionally, sensitivity to mechanical, thermal, and cold stimuli, along with anxiety-like behavior, were also measured. Our results indicated that spontaneous withdrawal following discontinuation of oxycodone produced an increase in total withdrawal signs after 60 and 120 mg/kg/day regimens of oxycodone administration. These signs were reversed by the administration of clinically approved medications for OUD. In general, both female and male mice showed similar profiles of somatic signs of spontaneous withdrawal. Spontaneous withdrawal also resulted in mechanical and cold hypersensitivity lasting for 24 and 14 days, respectively, and produced anxiety-like behaviors after 2 and 3 weeks following oxycodone removal. These results help validate a new model of oxycodone dependence, including the temporally distinct emergence of somatic, hyperalgesic, and anxiety-like behaviors, potentially useful for mechanistic and translational studies of opioid dependence.

Knowledge and Attitude of the General Public Toward Palliative Care in Jordan: A Cross-Sectional Study.

Palliative care is directed to relieve the symptoms of serious and life-threatening illnesses. Unfortunately, it's usually provided lately in the disease course in developing countries due to a lack of awareness about its concept, which deprives many patients of its benefits. This study aims to investigate the knowledge and attitude of the Jordanian general public toward palliative care. A cross-sectional study was conducted using an electronic questionnaire via social media platforms. Knowledge about palliative care was measured using the "Palliative Care Knowledge Scale" (PaCKS), whereas the attitude was measured using an edited version of the "Frommelt Attitudes Toward Care of the Dying -B(FATCOD-B)" tool. The inclusion criteria were adults older than 18 years old who live in Jordan. Any subject who was younger than 18 years old, refused to give informed consent, and working or studying in a healthcare-related profession was excluded. 329 respondents filled out the survey (females = 214 (65%), mean age = 32.7 ± (13.63) years). Only 67 respondents (20.4%) heard about palliative care previously. The average knowledge score (out of 13) was 6.8 (±4.2). The average attitude score (out of 5) was 3.0 (±.4). Higher knowledge self-evaluation, older age, and higher income were factors associated with a higher level of knowledge and favorable attitude toward palliative care. Our study showed a moderate knowledge and neutral attitude toward palliative care. Further awareness campaigns should be conducted to raise the awareness of the Jordanian society regarding the objectives of palliative care.

Effect of vitamin E on doxorubicin and paclitaxel-induced memory impairments in male rats.

PURPOSE: In addition to peripheral neuronal dysfunction, conventional chemotherapy can be associated with other neurological treatment-limiting adverse effects, including cognitive dysfunction, memory impairment, and anxiety, which are referred to as "chemobrain". This study aimed to investigate the effects of doxorubicin (DOX) and paclitaxel (PAC) on learning and memory in rats using radial arm water maze (RAWM) and investigated a potential beneficial effect of vitamin E (Vit. E). METHODS: Adult male rats were injected with four doses of 2 mg/kg/week DOX, or 2 mg/kg PAC every other day intraperitoneally. Vit. E was co-administered with these drugs in other groups to study its antioxidative effects. Using the RAWM, each rat was assessed for learning and memory performance through two sets of six trials separated by a 5-min rest period evaluating both short- and long-term effects on memory. RESULTS: There was no deficit in learning or long-term memory in both drug groups compared to control. However, rats in both drug groups made significantly more errors in all short-term memory trials. This effect was mitigated when Vit. E was co-administered with either drug. Moreover, PAC (but not DOX) induced hippocampal lipid peroxidation by increasing the levels of standard biomarker thiobarbituric acid reactive substances (TBARS). Interestingly, Vit. E prevented PAC-induced hippocampal oxidative stress. Furthermore, both DOX and PAC were correlated with reduction in Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus, which was overcome by the co-administration of Vit. E. CONCLUSION: There is a potential role of Vit. E in alleviating short-term memory impairment in rats exposed to chemotherapy, possibly by reducing hippocampal oxidative stress and neurodegeneration.

Preclinical comparison of antinociceptive effects between ibuprofen, diclofenac, naproxen, and acetaminophen on acid-stimulated body stretching and acid-depressed feeding behaviors in rats.

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient's and doctor's previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1-24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10-32 mg/kg), and naproxen (3.2-10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.

Healthcare students' mental and physical well-being during the COVID-19 lockdown and distance learning.

BACKGROUND: The sudden shift into distance learning during the coronavirus (COVID-19) lockdown might have impacted university students' well-being. OBJECTIVE: This study aimed to investigate undergraduate healthcare university students' health-related quality of life (HRQoL) and its predictors during COVID-19. METHODS: A cross-sectional study used an online self-administered questionnaire. The study targeted undergraduate medical, dental, pharmacy, and nursing students at Jordanian universities. Data collected included demographics,12-item Short Form health survey (SF-12), students' evaluation of distance learning, Neck Disability Index (NDI), Depression Anxiety Stress Scale (DASS21), and the International Physical Activity Questionnaire (IPAQ). Descriptive analyses were conducted to summarize primary outcome measures data. Predictors of HRQoL were determined using a multiple variable regression analysis. RESULTS: In total, 485 university students successfully completed this study with a mean age of 20.6 (±2.0). Participants' HRQoL level measured by SF-12 mean scores were 66.5 (±20.2) for physical health component and 44.8 (±21.2) for mental health component. The regression model explained 65.5% of the variation (r2 = 0.655, F = 127.8, P < 0.001) in participants' HRQoL. Factors significantly associated with HRQoL included depression, neck disability index score, stress, health self-evaluation, average of satisfaction with distance learning, IPAQ score, and weekly studying hours. CONCLUSIONS: This study showed that healthcare students had a relatively low level of HRQoL during COVID-19 pandemic in Jordan. Academic and non-academic factors associated with HRQoL were identified and should be considered by healthcare educational institutions for better academic planning in future similar pandemics.

Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats.

BACKGROUND: Tramadol is a widely used analgesic that activates mu-opioid receptors (MOR) and inhibits serotonin and norepinephrine transporters. This mixed pharmacology may limit both its own abuse potential and its modulation of abuse potential of other MOR agonists. AIMS: This study used an intracranial self-stimulation (ICSS) procedure to compare abuse-related effects produced by acute or repeated treatment with tramadol or morphine in rats. Abuse potential in ICSS procedures is indicated by a drug-induced increase (or 'facilitation') of ICSS responding. METHODS: Adult male Sprague-Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond on a lever for pulses of electrical brain stimulation. Tramadol effects were evaluated after acute administration (3.2-32 mg/kg) in the absence or presence of the opioid antagonist naltrexone, the CYP2D6 hepatic-enzyme inhibitor quinine or a combination of both. Additionally, both tramadol and morphine were also tested before and after repeated tramadol (32 mg/kg/day for six days) or repeated morphine (3.2 mg/kg/day for six days). RESULTS: Acute tramadol produced primarily ICSS rate-decreasing effects that were antagonised by naltrexone but not by quinine or naltrexone + quinine. Tramadol also produced little or no ICSS facilitation after repeated tramadol or repeated morphine, and repeated tramadol did not enhance ICSS facilitation by morphine. By contrast, morphine-induced ICSS facilitation was enhanced by repeated morphine treatment. CONCLUSIONS: These results suggest that tramadol has lower abuse potential than other abused MOR agonists and that repeated tramadol exposure produces relatively little enhancement of abuse potential of other MOR agonists.

Management of Sickle Cell Disease Pain among Adolescent and Pediatric Patients.

Management of sickle cell pain in adolescent and pediatric patients is inadequate, and the employment of proper management guidelines and practices are highly variable among different regions and populations. APPT, the multidimensional adolescent pediatric pain tool, promotes optimal pain management and introduces best practical guidelines for pain management. The goal of this study is to assess pain and pain management among young patients diagnosed with sickle cell disease (SCD) by introducing the APPT as a tool for pain management, and analyze factors contributing to pain management. Information relevant to demographic data, SCD characteristics, APPT assessment, and satisfaction of patients regarding pain management were collected using a structured questionnaire. Results showed that SCD is highly associated with gender (p = 0.022), consanguinity (p = 0.012), and number of surgeries (p = 0.013). Most patients (58.9%) indicated the involvement of more than six body areas affected during pain crisis. Severe pain was described by more than half the patients (55.6%), while moderate pain was reported by 31.1%. Most patients described their pain by sensory, affective, and temporal words. The number of painful areas, pain intensity, and use of descriptive pain words was correlated and interpreted by age, BMI, school absence, and number of surgeries. Results of this study could provide guidance to healthcare providers to improve current practices for SCD pain management in order to improve health outcomes and patients' satisfaction.

Effects of combined swimming exercise and non-steroidal anti-inflammatory drugs on inflammatory nociception in rats.

Pain is a growing health problem with an increasing prevalence, and represents a large burden worldwide. Pain control can be achieved through pharmacological and non-pharmacological (such as exercise) interventions. The prolonged use of analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs), is accompanied by numerous side effects. No previous studies have examined whether exercise may enhance the analgesic effect of NSAIDs. In the present study, the effect of ibuprofen and swimming exercise on nociception threshold were investigated using a rat model of inflammatory pain. A prophylactic swimming protocol and a treatment swimming protocol were used. In the two protocols, nociception was induced by intraplantar injection of Complete Freund's Adjuvant. The authors hypothesized that swimming exercise may enhance ibuprofen-induced antinociception. In the control group, nociception lasted for 17 days, and ibuprofen produced an antinociceptive effect at a dose of 32 mg/kg. However, swimming exercise enhanced ibuprofen-induced antinociception in the two swimming protocols. Notably, ibuprofen produced a significant increase in the nociception threshold at a dose of 10 mg/kg in the prophylactic swimming group. In addition, the duration of inflammation did not exceed 8 days under either swimming protocol. In conclusion, the combination of ibuprofen and swimming exercise was effective in controlling nociception in a rat model of inflammatory pain. Based on these observations, the combined use of exercise and ibuprofen may be a viable intervention for the control of chronic pain, and may decrease the potential for drug-induced side effects.

Morphometric Study of the Hard Palate and Its Relevance to Dental and Forensic Sciences.

This study was conducted to identify the morphometric features of the hard palate and to test the reliability of using palatal morphology in sex determination. Three hundred maxillary casts were collected from dental clinics in north Jordan. The age and gender of the patient and the serial number for each cast were recorded. The age range was 6 to 50 years old. A caliper was used to perform the following measurements: the length, width, and depth of the hard palate. In addition, the size, shape, and position of the incisive papilla were also determined. All measurements were done by a trained examiner who was able to perform the measurements in a reproducible manner. Statistical analysis showed that the mean palatal length, width, and depth, and size of dental papilla in both groups were the highest in males. The full logistic regression model including all the three predictors (length, width, and depth) indicated that the three parameters were significantly correlated with gender in the adult group. However, in the child group, only width and length were significantly (p=0.001, p > 0.042 respectively) correlated with gender. Regarding the shape and size of the incisive papilla, they were significantly different between males and females in both adult (p > 0.03) and child (p=0.001) groups. These findings might be potentially relevant to anthropological studies aiming at individual and/or sex identification. Moreover, the results might have clinical value in prosthodontics, especially in fabricating complete maxillary dentures for edentulous patients.

Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents.

RATIONALE: TRV130 (oliceridine; N-[(3-methoxythiophen-2-yl)methyl]-2-[(9 R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine) is a novel mu opioid receptor (MOR) agonist that preferentially activates G-protein versus ß-arrestin signaling pathways coupled to MORs. Prevailing evidence suggests that TRV130 and other G-protein-biased MOR agonists may produce therapeutic analgesic effects with reduced adverse effects compared to existing MOR agonists. OBJECTIVES: This study compared the effects of acute and repeated TRV130 administration on measures of antinociception, gastrointestinal function, and abuse liability in rodents. We hypothesized that TRV130 would produce robust and sustained antinociception and abuse-related effects during repeated treatment, but that tolerance would develop to gastrointestinal inhibition. METHODS: Antinociception was assessed using a warm-water tail-withdrawal procedure in mice. Gastrointestinal function was assessed in mice using an in vivo measure of fecal output and in vitro assays of colonic propulsion and of colon and ileum circular muscle contraction. Abuse liability was assessed in rats using an intracranial self-stimulation (ICSS) procedure. (+)-TRV130 was administered with acute and repeated dosing regimens, and (-)-TRV130 was also examined in the ICSS procedure to assess stereoselectivity. RESULTS: Acute (+)-TRV130 treatment produced robust antinociception, complete inhibition of gastrointestinal function, and weak abuse-related effects. Repeated (+)-TRV130 treatment failed to produce tolerance to antinociception or gastrointestinal inhibition, and abuse-related effects were enhanced by repeated treatment. Effects of acute and repeated (+)-TRV130 in these procedures resemble effects of morphine, with the exception that TRV130 antinociception was more resistant to tolerance. (-)-TRV130 was inactive. CONCLUSIONS: These results suggest that TRV130 retains undesirable constipating and abuse-related effects during repeated treatment despite its bias for G-protein signaling.

Effects of repeated morphine on intracranial self-stimulation in male rats in the absence or presence of a noxious pain stimulus.

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were 3 main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for 6 days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects.

Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the µ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats.

RATIONALE: Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists. OBJECTIVES: This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone. METHODS: Adult male Sprague-Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32-10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment. RESULTS: NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine. CONCLUSIONS: These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.

Effects of µ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of µ-agonist efficacy and noxious stimulus intensity.

Pain is associated with stimulation of some behaviors and depression of others, and µ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six µ-agonists that varied in efficacy at µ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All µ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All µ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy µ-agonist nalbuphine, but not the high-efficacy µ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective µ-opioid analgesics and reveal distinctions between opioids based on efficacy at the µ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.

Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats.

In preclinical research on pain and analgesia, noxious stimuli can stimulate expression of some behaviors (e.g. withdrawal reflexes) and depress others (e.g. feeding, locomotion, and positively reinforced operant responding). Tolerance to morphine antinociception is a robust and reliable phenomenon in preclinical assays of pain-stimulated behavior, but development of morphine tolerance in assays of pain-depressed behavior has not been studied. This study compared morphine antinociceptive tolerance in parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response in one group of rats and to depress operant responding for electrical brain stimulation (intracranial self-stimulation; ICSS) in another group of rats. Antinociception produced by morphine (1.0 mg/kg) was determined after a regimen of chronic treatment with either saline or morphine in separate subgroups of rats in each procedure. In rats receiving chronic saline, acid alone stimulated a stretching response and depressed ICSS, and both acid effects were blocked by 1.0 mg/kg morphine. Rats receiving chronic morphine displayed hyperalgesic responses to the acid noxious stimulus in both procedures. Complete tolerance developed to morphine antinociception in the assay of acid-stimulated stretching, but morphine retained full antinociceptive effectiveness in the assay of acid-depressed ICSS. These results suggest that morphine antinociception in an assay of pain-depressed behavior is relatively resistant to tolerance. More broadly, these results suggest that antinociceptive tolerance can develop at different rates or to different degrees for different measures of antinociception.

Abuse-related effects of µ-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure.

Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS 'facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS 'depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of µ-agonist efficacy and of previous µ-agonist exposure as determinants of µ-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy µ agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.

Role of µ-opioid receptor reserve and µ-agonist efficacy as determinants of the effects of µ-agonists on intracranial self-stimulation in rats.

The net effect of µ-opioid receptor agonists on intracranial self-stimulation (ICSS) in rats reflects an integration of rate-increasing and rate-decreasing effects. Previous opioid exposure is associated with tolerance to rate-decreasing effects and the augmented expression of abuse-related rate-increasing effects. This finding was replicated here with morphine. Subsequent studies then tested the hypothesis that opioid agonist-induced rate-decreasing effects require the activation of a larger relative fraction of µ receptors, and hence are more vulnerable to tolerance-associated reductions in receptor density than rate-increasing effects. Two sets of experiments were conducted to test this hypothesis. First, the effects of morphine on ICSS were examined after pretreatment with the irreversible µ antagonist ß-funaltrexamine to reduce the density of available µ receptors. Second, effects were examined for a range of µ opioids that varied in relative efficacy at µ receptors. The hypothesis predicted that (a) morphine, after ß-funaltrexamine treatment, or (b) low-efficacy µ agonists would mimic the effects of morphine tolerance to produce the reduced expression of rate-decreasing effects and enhanced expression of rate-increasing effects. Neither of these predictions were supported. These results indicate that µ agonist-induced facilitation and depression of ICSS may be mediated by distinct populations of µ receptors that respond differently to regimens of opioid exposure.

Effects of the δ opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats.

UNLABELLED: The delta opioid receptor agonist SNC80 produces both antinociceptive and antidepressant effects in rodents. This profile suggests that SNC80 may also reverse prodepressant effects of pain. Accordingly, this study compared SNC80 effects in complementary assays of pain-stimulated and pain-depressed behavior in rats. Intraperitoneal injection of dilute acid served as an acute noxious visceral stimulus in rats to stimulate abdominal stretching (a pain-stimulated behavior) or depress intracranial self-stimulation of the medial forebrain bundle (ICSS; a pain-depressed behavior). When administered once per week to minimize acute tolerance, SNC80 (1-10 mg/kg IP) decreased acid-stimulated stretching but had little effect on acid-induced depression of ICSS. More frequent SNC80 administration produced tolerance to SNC80 effects on acid-stimulated stretching, but unmasked antinociception in the assay of acid-depressed ICSS. SNC80 did not facilitate ICSS in the absence of pain, and effects of SNC80 were not duplicated by ARM390, a reputed delta agonist congener of SNC80 that does not internalize delta receptors. These findings support continued consideration of delta agonists as candidate analgesics to treat prodepressant effects of pain and illustrate the potential for diametrically opposite effects of drug treatments on preclinical measures of pain-stimulated and pain-depressed behavior. PERSPECTIVE: The delta opioid agonist SNC80 blocked pain-related depression of intracranial self-stimulation in rats, suggesting that delta agonists may be useful to treat prodepressant effects of pain. Repeated SNC80 produced tolerance to SNC80 antinociception in a conventional assay of pain-stimulated behavior but unmasked SNC80 antinociception in an assay of pain-depressed behavior.

Some determinants of morphine effects on intracranial self-stimulation in rats: dose, pretreatment time, repeated treatment, and rate dependence.

Intracranial self-stimulation (ICSS) is a procedure used to evaluate the abuse liability of drugs. The µ opioid receptor agonist morphine is an acknowledged drug of abuse, and this study examined factors that may influence expression of abuse-related morphine effects on ICSS in rats. Adult male rats were equipped with intracranial electrodes targeting the medial forebrain bundle, and 10 stimulus frequencies (56-158 Hz in 0.05 log increments) were available during each daily session under a continuous reinforcement schedule. The primary dependent variable was the ICSS rate at each frequency. Under baseline conditions, the ICSS rate increased with frequency. After acute morphine (1-10 mg/kg), rate-decreasing effects predominated at early pretreatment times (10-30 min) and rate-increasing effects predominated at later pretreatment times (100-180 min). Acute morphine effects dissipated after 300 min. Repeated morphine (3.2-18 mg/kg/day×7 days at each dose) produced tolerance to rate-decreasing effects, enhanced expression of rate-increasing effects, and enhanced rate dependency of morphine effects. Withdrawal from repeated morphine produced small but significant dose-dependent decreases in ICSS. These results show that the magnitude and valence of morphine effects on rates of ICSS in rats are strongly influenced by morphine dose and pretreatment time, history of morphine exposure, and baseline ICSS rate.