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.

Clinical, sinonasal, and long-term smell and taste outcomes in mildly symptomatic COVID-19 patients.

INTRODUCTION: Coronavirus 2019 disease (COVID-19) has variable clinical, sinonasal, and smell/taste outcomes. METHODS: Observational study was conducted at a tertiary hospital in Amman, Jordan. Demographic data, clinical presentation and smoking status were collected. Sinonasal symptoms, using Sino-Nasal Outcome Test (SNOT-22) Questionnaire, were evaluated. Smell/taste dysfunction was followed for three months. RESULTS: Ninety-Seven patients had satisfactory responses. Eighty-six patients were symptomatic (41 at presentation, and 45 during admission). Among those patients, 59.3% had cough, 52.3% sore throat and 48.8% fever. The most common initial symptom was sore throat. Shortness of breath and smell/taste dysfunction were significantly higher in females. Surprisingly, shortness of breath was more common in non-smokers. Smell/taste dysfunction affected 25.6% of patients, but was the first symptom in only one patient. Fourteen of 22 symptoms in SNOT-22 had significant increase. The overall average of symptoms scores increased from 0.472 to 1.034, with smell/taste dysfunction to have the most increment. The latter symptom recovered completely in 81% and dysgeusia developed in 9.5% at three months, and it recovered completely in all patients at six months. CONCLUSION: Although COVID-19 may produce severe lower airways disease, it has modest effect on nose and paranasal sinuses. Moreover, smell/taste dysfunction is a prominent symptom, but it usually recovers dramatically.

Role of cannabinoid receptor 1 and the peroxisome proliferator-activated receptor α in mediating anti-nociceptive effects of synthetic cannabinoids and a cannabinoid-like compound.

Osteoarthritis (OA) is characterized by cartilage degeneration, subchondral sclerosis, and pain. Cannabinoids have well-established anti-nociceptive properties in animal models of chronic pain. The aim of this study is to evaluate the anti-nociceptive effects of synthetic cannabinoids (WIN-55,212 and HU210) and the cannabinoid-like compound palmitoylethanolamide (PEA) in rat models of OA and to assess the role of cannabinoid receptor 1 (CB1) and the peroxisome proliferator-activated receptor α (PPARα) in mediating these effects. Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint was used as a model of osteoarthritis. The von Frey filament test and weight-bearing difference were used to assess the anti-nociceptive effects of WIN-55,212, HU210, and PEA on MIA-induced OA in rats. Open-field locomotor activity system was used confirm the analgesic effects of those compounds. HU210, WIN55, 212, and PEA in a dose-dependent manner restored the paw withdrawal threshold (PWT) and the weight-bearing difference induced by MIA injection. SR141716A (a CB1 antagonist) significantly reversed the anti-nociceptive effects of all the administered drugs in terms of PWT. However, in terms of weight-bearing difference, SR141716A significantly reduced the anti-nociceptive effect of HU210 but not PEA or WIN55, 212. GW6471 (a PPARα antagonist) significantly reversed the anti-nociceptive effects of PEA but not those of HU210 or WIN55, 212. HU210, WIN55, 212 and PEA significantly restored the MIA-induced reduction in locomotor activity. In conclusions, both CB1 and PPARα receptors are involved in mediating pain in osteoarthritis. Therefore, targeting these receptors may be of great clinical value.

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.

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.

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.

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.

Long-term effects of neonatal pain and sucrose treatment.

Purpose: In neonatal intensive care units, applying sucrose solution for analgesia is now a routine treatment for mild procedural pain. Studies of animal and human infants provide clear evidence of benefits in the short term, but few studies have investigated the long term benefits. Thus, we determined whether sucrose could ameliorate painful stimulation during infancy in Sprague-Dawley rats and also explored the long-term effects of repeated sucrose administration during infancy. Female and male rats were included to investigate sex-related differences. Methods: Rat pups were stimulated either with painful or tactile stimuli for the first 14 days of their lives. Pups were pretreated either with sucrose or not treated before stimulation. Behavioral tests were conducted during adolescence and adulthood. Hotplate, rotarod, open field, elevated plus maze, and radial arm water maze tests were employed to assess the behavioral consequences of early life manipulations and treatments. Results: Painful stimulation during infancy increased the sensitivity to pain later in life, and sucrose did not remedy this effect. Motility, coordination, anxiety, and cognition tests in adulthood obtained mixed results. Pain during infancy appeared to increase anxiety during adulthood. Learning and memory in adulthood were affected by pain during infancy, and sucrose had a negative effect even in the absence of pain. No sex-related differences were observed in any of the behavioral tests by employing this model of neonatal pain. Conclusion: Painful stimulation during infancy resulted in deficiencies in some behavioral tests later in life. Sucrose pretreatment did not mitigate these shortcomings and it actually resulted in negative outcomes.

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.

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.

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.

Analgesic Effects and Impairment in Locomotor Activity Induced by Cannabinoid/Opioid Combinations in Rat Models of Chronic Pain.

Both opioids and cannabinoids have well-known antinociceptive effects in different animal models of chronic pain. However, unwanted side effects limit their use. The aim of this study is to evaluate the antinociceptive effect of combining synthetic cannabinoids with subtherapeutic doses of opioids, and to evaluate the effects of these drugs/combinations on rat's locomotor activity. Intra-plantar injection of Complete Freund's Adjuvant (CFA) into the left hindpaw and intraperitoneal injection of streptozotocin (STZ) were used to induce inflammatory and diabetic neuropathic pain in adult male Sprague-Dawley rats, respectively. Von Frey filaments were used to assess the antinociceptive effects of opioids (morphine and tramadol) and the synthetic cannabinoids (HU210 and WIN55212) or their combinations on CFA and STZ-induced mechanical allodynia. Open field test was used to evaluate the effect of these drugs or their combinations on locomotion. HU210 and WIN55212 did not produce significant antinociceptive effect on inflammatory pain while only the maximal dose of HU210 (1 mg/kg) was effective in neuropathic pain. Only the maximal doses of morphine (3.2 mg/kg) and tramadol (10 mg/kg) had significant anti-allodynic effects in both models. Tramadol (1 mg/kg) enhanced the antinociceptive effects of WIN55212 but not HU210 in neuropathic pain with no effect on inflammatory pain. However, in open field test, the aforementioned combination did not change tramadol-induced depression of locomotion. Tramadol and WIN55212 combination produces antinociceptive effects in neuropathic but not inflammatory pain at low doses with no additional risk of locomotor impairment, which may be useful in clinical practice.

Impairment in locomotor activity as an objective measure of pain and analgesia in a rat model of osteoarthritis.

A major problem with current animal models of pain is their lack of face validity and their vulnerability for false positive results. The present study evaluated the efficacy of the open field locomotor system, as an objective measure of pain-related behavior and analgesic efficacy in rodents. Adult, male, Sprague-Dawley rats (180-250 g) received intra-articular injections of monoiodoacetate (MIA; 1 mg) in the left knee joint. Mechanical allodynia using von Frey filaments, the weight bearing difference test and the open field locomotor activity test were performed every other day for 21 days, following the MIA injection. The antinociceptive effects of ibuprofen (50 and 100 mg/kg) on the MIA-induced nociception were also evaluated. MIA induced a significant reduction in the paw withdrawal threshold (PWT) and a significant alteration in the weight bearing difference compared with control rats. Similarly, MIA induced a significant reduction in locomotor activity, with respect to X total counts, that represent the overall locomotor activity in the horizontal plane, and X ambulatory counts, which in turn represent small scale movements, such as scratching and grooming, and lastly, Z total counts, that represent rearing or standing. Both doses of ibuprofen resulted in a significant reversal of the MIA-induced alterations in PWT and weight bearing difference. Furthermore, the two doses of ibuprofen resulted in a significant reversal of the MIA-induced reduction in locomotor activity, with respect to X ambulatory counts, but not Z total counts. Only the higher dose of ibuprofen reversed the X total counts. The open field locomotor system may successfully be used to predict the analgesic efficacy of compounds in models of joint inflammation and osteoarthritis.

The desensitization of the transient receptor potential vanilloid 1 by nonpungent agonists and its resensitization by bradykinin.

Transient receptor potential vanilloid type-1 (TRPV1) channels have crucial roles in inflammatory hyperalgesia. Different inflammatory mediators can modulate TRPV1 sensitization. Bradykinin is an algogenic substance released at the site of inflammation. The aim of the present study is to investigate the desensitization of TRPV1 receptor by nonpungent agonists and to determine how bradykinin and prostaglandin E2 receptors (EP3 and EP4) modulate the resensitization of TRPV1 receptor after being desensitized by nonpungent agonists. Tail flick test was used to investigate capsaicin-induced thermal hyperalgesia and the desensitization of TRPV1 by the nonpungent agonists (olvanil and arvanil) in male BALB/c mice weighed (22-25 g). Resensitization of TRPV1 by bradykinin and the role of prostaglandin receptors in mediating sensitization of TRPV1 were also investigated. Intraplantar injection of capsaicin (0.3 µg) produced a robust thermal hyperalgesia in mice, while olvanil (0.3 µg) or arvanil (0.3 µg) produced no hyperalgesia, emphasizing their lack of pungency. Olvanil and arvanil significantly attenuated capsaicin-induced thermal hyperalgesia in mice. Bradykinin significantly reversed the desensitizing effects of arvanil, but not olvanil. EP4 but not EP3 receptors mediate the sensitization of TRPV1 By bradykinin in vivo. The present study provides evidence for a novel signaling pathway through which bradykinin can regulate the TRPV1 ion channel function via EP4 receptor.

Effects of intraplantar administration of Complete Freund's Adjuvant (CFA) on rotarod performance in mice.

BACKGROUND AND AIMS: Preclinical animal models are crucial to study pain mechanisms and assess antinociceptive effects of medications. One major problem with current animal behavioral models is their lack of face validity with human nociception and the vulnerability for false-positive results. Here, we evaluated the usefulness of rotarod as a new way to assess inflammatory nociception in rodents. METHODS: Adult male mice were injected with saline or Complete Freund's Adjuvant (CFA) in the left hindpaws. Mechanical allodynia and rotarod performance were evaluated before and after the administration of CFA. Mechanical allodynia was measured using von Frey filaments. Long-term effect of CFA on rotarod performance was also assessed for 2 weeks. RESULTS: Our results showed that CFA administration decreased pain threshold and increased sensitivity to von Frey filaments compared to control group. In rotarod experiments, the starting speed of the rod rotation started at four RPM, and accelerated until it reached 40 RPM in 5 min. Rotarod performance was enhanced from day to day in the control group. However, rotarod performance in CFA group was attenuated after CFA administration, which was significant after 24 h compared to vehicle. This attenuation was blocked by ibuprofen. Haloperidol administration (positive control) produced similar results to CFA administration. CFA did not produce significant attenuation of rotarod performance after 1 week post-injection. CONCLUSIONS: Collectively, our findings could encourage the use of rotarod assay to measure acute (but not chronic) inflammatory nociception as a useful tool in rodents.

Early and late anti nociceptive effects of sucrose on neonatal inflammatory pain in rats: Comparison to a non-steroidal anti-inflammatory drug.

Management of neonatal pain is not only ethical but is also essential. Barriers to pain management in infants include lack of safe and effective medications and fear of adverse effects of conventional pain medications. Sweet solutions given intraorally have been shown to reduce pain behaviors and associated symptoms. Sucrose and other sweet solutions are being increasingly used at the NICUs and immunization clinics. Sucrose for mild invasive procedures is effective and safe for those procedures that need to be repeated multiple times during the day. Only few studies examine the efficacy of sucrose for the management of inflammatory pain during infancy. In this study, Complete Freund's Adjuvant (CFA) was used to induce inflammation in 5-day-old rat pups; CFA also produces inflammation that lasts for more than a day, thus can also be a model for chronic pain. Sucrose or ibuprofen was given to subset of pups shortly after CFA intraplantar injections. Thermal as well as mechanical pain sensitivity was assessed on subsequent days as well as during adolescence and early adulthood. Sucrose and ibuprofen were both effective in preventing hyperalgesia and allodynia produced by CFA. Interestingly, sucrose was even more effective than ibuprofen, and the analgesic effects continued further to adolescence and adult life of the rats. Thus, and according to the results of this study, sucrose seems to be just as effective for inflammatory pain as Ibuprofen. In addition, sucrose protects against later-in-life hypersensitivity consequences to neonatal pain.

Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats.

Chronic pain is a persistent and debilitating health problem. Although the use of analgesics such as opioids is useful in mitigating pain, their prolonged use is associated with unwanted effects including abuse liability. This study assesses the antinociceptive effect of combining subtherapeutic doses of two opioids (morphine or tramadol) with the synthetic cannabinoid CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan -2-yl)phenol). It also evaluates the associated adverse effects of these drugs and combinations. Adult male rats were injected with intraplantar complete Freund's adjuvant (CFA) to produce mechanical allodyia. Antinociceptive effect of morphine, tramadol, the synthetic cannabinoid CP55940, or their combinations was evaluated three to nine days post-CFA injections. Intracranial self-stimulation (ICSS) was utilized to evaluate the abuse liability of these drugs or their combinations. All drugs alone produced a dose-dependent antinociceptive effect. Morphine produced minimal effect on ICSS, but both tramadol and CP55940 produced dose-dependent depression of ICSS. Morphine at a dose of 0.32 mg/kg enhanced the antinociceptive effects of CP55940, in that, CP55940 produced antinociception at a lower dose (0.1 mg/kg) when compared to the vehicle. The aforementioned combinations did not change CP55940-induced depression of ICSS. On the other hand, tramadol failed to enhance the antinociceptive effect of CP55940. Our data suggest that combining CP55940 with morphine, but not tramadol, shows a better antinociceptive profile with no additional risk of abuse liability, which represents a potential pain management approach.

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.