Freund's Complete Adjuvant-induced Inflammation Research Articles

Cyclodextrin nanosponges based site-retentive controlled release system for treatment of rheumatic arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammatory disease of joints. Methotrexate (MTX) is the choice of drug in the treatment of RA due to its prominent immunosuppressant effect and anti-inflammatory effect via an increase in cyclic adenosine monophospate (cAMP) and adenosine-based activity. Our study investigated the local effect of MTX loaded nanosponges in the gel (nanogel) which could be of potential for solubility enhancement, prolonged drug release and retention time, reduced systemic adverse effect, and enhanced anti-arthritic activity. MTX loaded β-cyclodextrin based nanosponges (MTX-NS) were successfully prepared and characterized by FTIR and NMR. Prepared MTX-NS was evaluated for drug loading, particle size, and morphology. Subsequently, MTX-NS was formulated in a gel-based system, which was evaluated for gelation time, gelation temperature, in-vitro cell line study, and in-vitro drug release. A sustained drug release profile was observed with the developed nanogel. The cell viability of the MTX-NS and nanogel was determined in macrophage cells (RAW264.7) which indicated that nanogel was found to be effective and safe compared to MTX-NS and MTX. The scratch assay indicated that cell migration was significantly inhibited with MTX-NS. Further, the in-vivo study of nanogel was performed using Freund's complete adjuvant-induced inflammation model that confirms the superior anti-arthritic activity of the developed formulation.

Antiarthritic and Antihyperalgesic Properties of Ethanolic Extract from Gomphrena celosioides Mart. (Amaranthaceae) Aerial Parts.

Gomphrena celosioides Mart. (Amaranthaceae) is used in folk medicine as a natural analgesic, and in Brazil, the species of genus Gomphrena is used for rheumatism. However, scientific evidence which supports its popular use as an analgesic is scarce. This study assessed the antiarthritic and antihyperalgesic activities of the ethanolic extract obtained from G. celosioides aerial parts on Swiss or C57BL/6 mice. The antiarthritic and antihyperalgesic potential of Gomphrena celosioides was evaluated using paw edema, mechanical hyperalgesia, cold allodynia, carrageenan-induced pleurisy, articular inflammation zymosan-induced, Freund's complete adjuvant-induced inflammation zymosan-induced peritonitis, and carrageenan-induced adhesion and rolling experiment models. All doses of G. celosioides (300, 700, and 1000 mg/kg) significantly reduced edema formation in all the intervals evaluated, whereas the mechanical hyperalgesia was reduced 3 hours after the carrageenan injection. The cold hyperalgesia was significantly decreased 3 (700 mg/kg) and 4 hours (700 and 1000 mg/kg) after the carrageenan injection. Ethanolic extract of G. celosioides at 1000 mg/kg reduced the total leukocyte number, without interfering in the protein extravasation in carrageenan-induced pleurisy model. Ethanolic extract of G. celosioides (300 mg/kg) was also able to reduce significantly the leukocyte migration in zymosan-induced articular edema, while a reduction of the adhesion and migration and leukocyte rolling was induced by the ethanolic extract of G. celosioides (300 mg/kg) in zymosan-induced peritonitis. In Freund's complete adjuvant-induced inflammation model, an edema formation and mechanical hyperalgesia reduction were induced by the ethanolic extract of G. celosioides on day 22, whereas the cold allodynia was reduced on day 6 of treatment with the extract. These results show that ethanolic extract of G. celosioides has antihyperalgesic and antiarthritic potential in different acute and persistent models, explaining, at least in part, the ethnopharmacological relevance of this plant as a natural analgesic agent.

Fentanyl decreases discharges of C and A nociceptors to suprathreshold mechanical stimulation in chronic inflammation

An essential component of mechanical hyperalgesia resulting from tissue injury is an enhanced excitability of nociceptive neurons, termed mechanical sensitization. Local application of opioids to inflamed rat paws attenuates mechanical hyperalgesia and reduces electrical excitability of C-fiber nociceptors in acute injury. Here, we examined the effects of the opioid receptor agonist fentanyl on the mechanical coding properties of not only C- but also A-fiber nociceptors innervating the rat hind paw in a model of chronic pain, i.e., 4 days after Freund's complete adjuvant-induced inflammation. The peripheral mechanosensitive terminals of C-fibers (n = 143), A-fibers (n = 79), and low-threshold mechanoreceptors (n = 25) were characterized using the in vitro skin-nerve preparation from the saphenous nerve. Although mechanical activation thresholds were not changed, discharges to suprathreshold mechanical stimuli were elevated significantly in both A- and C-fiber nociceptors from inflamed tissue. In addition, the proportion of nociceptors as well as the frequency of spontaneous discharges in A (14% vs. 0%)- and C (28% vs. 8%)-fibers were increased in inflamed compared with normal tissue. Fentanyl inhibited responses to suprathreshold stimuli in a significantly higher proportion of not only C (36% vs. 7%)- but also A (41% vs. 8%)-fibers in inflamed tissue in a naloxone-reversible and concentration-dependent manner. Our results demonstrate that mechanical sensitization persists in chronic inflammation, in correlation with behavioral hyperalgesia. Opioid sensitivity of both A- and C-fibers is markedly augmented. This is consistent with an upregulation or enhanced functionality of opioid receptors located at the peripheral terminals of sensitized nociceptors.

Regulation and function of spinal and peripheral neuronal B 1 bradykinin receptors in inflammatory mechanical hyperalgesia

Activation of either B 1 or B 2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B 2 agonists activate sensory neurones directly, B 1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B 1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B 1 receptors in inflammatory hyperalgesia. Therefore we have examined B 1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B 1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B 1 protein in ipsilateral dorsal root ganglia . In behavioural experiments, the B 1 antagonist desArg 10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B 1 agonist, desArg 9BK, did not affect paw withdrawal thresholds in naı̈ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg 9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B 1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II. in vivo characterization in rat models of inflammatory and neuropathic pain.

The vanilloid receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) is a recently described inhibitor of capsaicin- and acid-mediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 micro g of capsaicin. In rats with Freund's complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.