cr4056 and Pain

CR4056 is a first-in-class imidazoline-2 (I. Effects of CR4056 on bradykinin-induced PKCε translocation were studied in rat sensory neurons by immunocytochemistry. PKCε activation was investigated by immunohistochemistry analysis of DRG from complete Freund's adjuvant-treated animals developing local hyperalgesia. The analgesic activity of CR4056 was tested on the same animals.. CR4056 inhibited PKCε translocation with very rapid and long-lasting activity. CR4056 decreased hyperalgesia and phospho-PKCε immunoreactivity in the DRG neurons innervating the inflamed paw. The effect of CR4056 on PKCε translocation was blocked by pertussis toxin, implying that the intracellular pathways involved G. Our results demonstrate that CR4056 shares the ability to inhibit PKCε translocation with other analgesics. Whether the inhibition of PKCε involves binding to specific subtype(s) of I

Topics: Amino Acid Sequence; Analgesics; Animals; Cell Membrane; Cells, Cultured; Dose-Response Relationship, Drug; Freund's Adjuvant; Humans; Imidazoles; Imidazoline Receptors; Inflammation; Male; Pain; Phosphorylation; Protein Kinase C-epsilon; Quinazolines; Rats; Rats, Wistar; Sensory Receptor Cells

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.

Topics: Analgesics; Animals; Benzofurans; Depression; Disease Models, Animal; Fibromyalgia; Hyperalgesia; Idazoxan; Imidazoles; Imidazoline Receptors; Imidazolines; Male; Pain; Pain Measurement; Quinazolines; Rats; Rats, Sprague-Dawley; Reserpine

The imidazoline I2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 μl) were quantified after treatment with I2 receptor agonists alone or in combination with the I2 receptor antagonist idazoxan. Anatomical mediation was studied by locally administering 2-BFI into the plantar surface or into the right lateral ventricle through cannulae (intracerebroventricular). The locomotor activity was also examined after central (intracerebroventricular) administration of 2-BFI. 2-BFI (1-10 mg/kg, intraperitoneal) and BU224 (1-10 mg/kg, intraperitoneal) attenuated the spontaneous flinching response observed during 10 min (phase 1) and 20-60 min (phase 2) following formalin treatment, whereas CR4056 (1-32 mg/kg, intraperitoneal) decreased only phase 2 flinching response. The I2 receptor antagonist idazoxan attenuated the antinociceptive effects of 2-BFI and BU224 during phase 1, but not phase 2. Peripheral administration of 2-BFI (1-10 mg/kg, intraplantar) to the hind paw of rats had no antinociceptive effect. In contrast, centrally delivered 2-BFI (10-100 µg, intracerebroventricular) dose-dependently attenuated phase 1 and phase 2 flinching at doses that did not reduce the locomotor activity. Together, these data revealed the differential antinociceptive effects of I2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I2 receptor agonist-induced antinociceptive actions.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazoles; Imidazoline Receptors; Injections, Intraperitoneal; Injections, Intraventricular; Locomotion; Male; Pain; Pain Measurement; Quinazolines; Rats; Rats, Sprague-Dawley; Time Factors