naloxone and Arthralgia

Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD.. Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue.. MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β-endorphin post-MIA which correlated with impaired allodynia.. These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD.. This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Analgesics; Analgesics, Opioid; Animals; Arthralgia; Behavior, Animal; beta-Endorphin; Chronic Pain; Disease Models, Animal; Enzyme Inhibitors; Gabapentin; Humans; Hyperalgesia; Injections, Intra-Articular; Iodoacetic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphine; Naloxone; Narcotic Antagonists; Osteoarthritis; Pain Measurement; Pain Threshold; Quality of Life; Spinal Cord

Exercise is commonly recommended for patients with osteoarthritis (OA) pain. However, whether exercise is beneficial in ameliorating ongoing pain that is persistent, resistant to nonsteroidal antiinflammatory drugs (NSAIDs), and associated with advanced OA is unknown.. Rats treated with intraarticular (IA) monosodium iodoacetate (MIA) or saline underwent treadmill exercise or remained sedentary starting 10 days postinjection. Tactile sensory thresholds and weight bearing were assessed, followed by radiography at weekly intervals. After 4 weeks of exercise, ongoing pain was assessed using conditioned place preference (CPP) to IA or rostral ventromedial medulla (RVM)-administered lidocaine. The possible role of endogenous opioids in exercise-induced pain relief was examined by systemic administration of naloxone. Knee joints were collected for micro-computed tomography (micro-CT) analysis to examine pathologic changes to subchondral bone and metaphysis of the tibia.. Treadmill exercise for 4 weeks reversed MIA-induced tactile hypersensitivity and weight asymmetry. Both IA and RVM lidocaine D35, administered post-MIA, induced CPP in sedentary but not exercised MIA-treated rats, indicating that exercise blocks MIA-induced ongoing pain. Naloxone reestablished weight asymmetry in MIA-treated rats undergoing exercise and induced conditioned place aversion, indicating that exercise-induced pain relief is dependent on endogenous opioids. Exercise did not alter radiographic evidence of OA. However, micro-CT analysis indicated that exercise did not block lateral subchondral bone loss or trabecular bone loss in the metaphysis, but did block MIA-induced medial bone loss.. These findings support the conclusion that exercise induces pain relief in advanced, NSAID-resistant OA, likely through increased endogenous opioid signaling. In addition, treadmill exercise blocked MIA-induced bone loss in this model, indicating a potential bone-stabilizing effect of exercise on the OA joint.

Topics: Anesthetics, Local; Animals; Arthralgia; Arthritis, Experimental; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Hyperalgesia; Injections, Intra-Articular; Iodoacetic Acid; Knee Joint; Lidocaine; Male; Medulla Oblongata; Naloxone; Narcotic Antagonists; Osteoarthritis, Knee; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Tibia; Weight-Bearing; X-Ray Microtomography

We investigated the anti-inflammatory activity of strontium ranelate (SR) in arthritis models.. Rats received 1 mg zymosan (Zy) or saline intra-articularly. Other groups were subjected to anterior cruciate ligament transection in the right knee, as an osteoarthritis (OA) model, or a sham procedure. Joint pain was assessed using the articular incapacitation and paw-pressure tests. Cell influx and cytokines were measured in joint exudates.. Groups received either SR (30-300 mg/kg per os) or saline.. SR dose-dependently and significantly inhibited joint pain in both Zy and OA models, while not altering cell influx. Naloxone administration significantly reversed SR analgesia. SR significantly reduced levels of Interleukin-1β and tumor necrosis factor-α in Zy arthritis, whereas those of cytokine-induced neutrophil chemoattractant (CINC)-1 were not altered.. SR provides analgesia in arthritis that is associated to inhibition of the release of inflammatory cytokines into inflamed joints. This effect is abrogated by administration of the opioid antagonist naloxone.

Topics: Analgesics, Non-Narcotic; Animals; Arthralgia; Chemokine CXCL1; Cytokines; Dose-Response Relationship, Drug; Injections, Intra-Articular; Interleukin-1beta; Joints; Naloxone; Narcotic Antagonists; Osteoarthritis; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid; Thiophenes; Tumor Necrosis Factor-alpha

We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis.. Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg·kg⁻¹ per os) or saline 2 h after intra-articular zymosan. Other groups received the µ-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil.. Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-α release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil.. Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-α release in inflamed joints.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthralgia; Arthritis, Experimental; Carbolines; Chemokine CXCL1; Chemokines; Cyclic GMP; Guanylate Cyclase; Injections, Intra-Articular; Interleukin-1; Joints; Male; Naloxone; Narcotic Antagonists; Neutrophils; Nociception; Osteoarthritis; Oxadiazoles; Quinoxalines; Rats; Rats, Wistar; Tadalafil; Tumor Necrosis Factor-alpha; Zymosan

Although N-methyl-d-aspartate (NMDA) receptor antagonists potentiate antinociceptive effects induced by various exogenous opioids at the spinal, supraspinal, or peripheral level, less is known regarding the interaction between NMDA and endogenous opioids in antinociception. We therefore assessed the effects of NMDA receptor antagonists on endogenous opioids in antinociception at the peripheral level by testing the ability of the locally administered receptor antagonists to modify pain-related behavior induced by carrageenan injection into the knee joint. The NMDA receptor antagonist AP-5 or the exogenous opioid morphine was injected intra-articularly before carrageenan injection and 5h after carrageenan injection, respectively. We evaluated whether intra-articular injection of the opioid receptor antagonist naloxone reversed the analgesic effect of AP-5. In addition, we tested the effects of AP-5 on carrageenan-induced levels of the beta-endorphin protein in dorsal root ganglia (DRG), saphenous nerve and synovial membrane. We found that AP-5 prevented and morphine reversed carrageenan-induced pain-related behavior. Intriguingly, injection of naloxone 5h after carrageenan injection reversed the antinociceptive effects of AP-5 pre-treatment, although naloxone alone had no effect on carrageenan-induced pain-related behavior. Western blots showed that AP-5 pre-treatment followed by carrageenan injection resulted in a higher level of beta-endorphin protein in the DRG and saphenous nerve, but not in the synovial membrane, than that observed following saline control treatment. These results suggest that inhibition of the NMDA receptor unmasks antinociception induced by endogenous opioids at the peripheral level, partly through the increased protein level of the endogenous mu-opioid peptide beta-endorphin in DRG and saphenous nerve.

Topics: 2-Amino-5-phosphonovalerate; Analgesics, Opioid; Animals; Arthralgia; Arthritis; beta-Endorphin; Carrageenan; Drug Synergism; Excitatory Amino Acid Antagonists; Ganglia, Spinal; Male; Morphine; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Measurement; Pain Threshold; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synovial Membrane

The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.

Topics: Analgesics; Animals; Arthralgia; Arthritis, Experimental; Chemokine CXCL1; Chemokines, CXC; Exudates and Transudates; Immunohistochemistry; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-1; Interleukin-6; Knee Joint; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Synovial Membrane; Thalidomide; Tumor Necrosis Factor-alpha; Zymosan

This study describes a novel method for direct subarachnoid drug delivery to the medullary dorsal horn region of rats, without introducing a catheter. The reliability of the method was demonstrated by a pharmacological validation; that is, morphine administration to the medullary region blocked the nociceptive response to formalin injected in the temporomandibular joint (TMJ) region, an effect that was prevented by co-administration of naloxone. The method proposed offers many advantages over the existing methods for medullary drug delivery with catheter implantation. It is easy to be employed, it does not induce any sign of motor impairment, and it does not require the neck surgery performed to implant a catheter in the medullary dorsal horn region. Therefore, it is a useful method for subarachnoid drug delivery in behavioral trigeminal pain studies, particularly when nociceptive behavioral measures that require normal neck muscle activity to occur, such as head withdraw or head flinch, are evaluated.

Topics: Analgesics, Opioid; Animals; Arthralgia; Drug Delivery Systems; Head Movements; Male; Medulla Oblongata; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Neck Muscles; Neurosurgical Procedures; Nociceptors; Pain Measurement; Rats; Rats, Wistar; Subarachnoid Space; Syringes; Temporomandibular Joint Disorders; Trigeminal Caudal Nucleus

Topics: Aged; Analgesics, Opioid; Arthralgia; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Drug Combinations; Humans; Middle Aged; Musculoskeletal Diseases; Naloxone; Osteoarthritis; Pain Measurement; Patient Satisfaction; Tilidine; Treatment Outcome