dynorphins and Osteoarthritis

Osteoarthritis is the most common form of arthritis, and pain relief with opioid-like drugs is a commonly used therapeutic for osteoarthritic patients. Recent studies published by our group showed that the kappa opioid receptor (KOR) is highly expressed during human development in joint-forming cells. However, the precise role of this receptor in the skeletal system remains elusive. The main aim of the current study was to investigate the role of KOR signaling in synovial and cartilaginous tissues in pathological conditions. Our data demonstrate that KOR null mice exhibit accelerated cartilage degeneration after injury when compared with WT mice. Activation of KOR signaling increased the expression of anabolic enzymes and inhibited cartilage catabolism and degeneration in response to proinflammatory cytokines such as TNF-α. In addition, selective KOR agonists increased joint lubrication via the activation of cAMP/CREB signaling in chondrocytes and synovial cells. Taken together, these results demonstrate direct effects of KOR agonists on cartilage and synovial cells and reveals a protective effect of KOR signaling against cartilage degeneration after injury. In addition to pain control, local administration of dynorphin or other KOR agonist represents an attractive therapeutic approach in patients with early stages of osteoarthritis.

Topics: Adult; Animals; Cartilage; Chondrocytes; Dynorphins; Fetus; Humans; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Osteoarthritis; Receptors, Opioid, kappa; Signal Transduction; Synovial Fluid

The aim of the present study was to evaluate whether eugenol, the main constituent of clove oil, has the capacity to provide analgesia in the monoiodoacetate-induced rat model of osteoarthritis. Animals (n = 6/group) received either eugenol (20 or 40 mg/kg) or a vehicle by gavage. Daily administrations were initiated 2 days post osteoarthritis induction and continued for the duration of the study (4 weeks). Gait analysis was performed using the CatWalk method and secondary mechanical allodynia was assessed with von Frey filaments. Selected spinal cord peptides (substance P, calcitonin gene-related peptide and dynorphin) were quantified by mass spectrometry. Significant changes were identified in dynamic gait parameters (swing speed, swing phase duration and duty cycle) of the affected limb following 40 mg/kg eugenol treatment compared with the vehicle (p < 0.05). Von Frey results revealed significant differences between the 40 mg/kg treatment and the vehicle group during the first and the third week of the study (p < 0.02). Spinal pain-related peptide analysis revealed a decreased content of substance P and CGRP accompanied by an increase of dynorphin in animals treated with 40 mg/kg eugenol. These results suggest a therapeutic potential of eugenol to alleviate osteoarthritis-related pain.

Topics: Analgesics; Animals; Calcitonin Gene-Related Peptide; Clove Oil; Disease Models, Animal; Dynorphins; Eugenol; Gait; Hyperalgesia; Iodoacetic Acid; Knee Joint; Male; Osteoarthritis; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P

Animal models are useful to evaluate pharmacological therapies to alleviate joint pain. The present study characterized central neuropeptides modulation in the monoiodoacetate (MIA) rat model. Animals receiving a single 3mg MIA injection were euthanized at 3, 7, 14, 21 and 28 days post injection. Spinal cords were analyzed by liquid chromatography ion trap mass spectrometry. Up-regulations of the calcitonin gene-related peptide and substance P were observed starting on days 7 and 28 respectively, whereas big dynorphin(₁₋₃₂) content decreased significantly on day 14 in comparison to control animals (P<0.05). Preclinical drug evaluations using this model should be conducted between 7 and 21 days post injection when the lesions resemble most to human osteoarthritis.

Topics: Animals; Calcitonin Gene-Related Peptide; Chromatography, Liquid; Disease Models, Animal; Dynorphins; Enzyme Inhibitors; Humans; Iodoacetic Acid; Knee Joint; Male; Neuropeptides; Osteoarthritis; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P; Tandem Mass Spectrometry; Time Factors