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Modulation of imidazoline I2 binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats.

Lanza M, Ferrari F, Menghetti I, Tremolada D, Caselli G - Br. J. Pharmacol. (2014)

Bottom Line: Analgesic effects of CR4056 were completely suppressed by the non-selective imidazoline I2 /α2 -adrenoceptor antagonist idazoxan, were partially reduced (~30%; P < 0.05) by the selective α2 -adrenoceptor antagonist yohimbine, but were not influenced by the non-selective I1 /α2 -adrenoceptor antagonist efaroxan or by the μ opioid receptor antagonist naloxone.When CR4056 and morphine were combined, their median effective doses were lower than expected for additive effects, both in males and in females.CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof-of-concept study in patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., Monza, MB, Italy.

No MeSH data available.


Related in: MedlinePlus

(A) Anti-hyperalgesic effect of CR4056 on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). CR4056 was orally administered 24 h after surgery. Naproxen (30 mg·kg−1; oral) was used as comparison. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group). (B) Anti-hyperalgesic effects of morphine on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). Morphine was subcutaneously administered 24 h after surgery. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
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fig01: (A) Anti-hyperalgesic effect of CR4056 on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). CR4056 was orally administered 24 h after surgery. Naproxen (30 mg·kg−1; oral) was used as comparison. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group). (B) Anti-hyperalgesic effects of morphine on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). Morphine was subcutaneously administered 24 h after surgery. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).

Mentions: Twenty-four hours after surgery, male rats showed hyperalgesia to mechanical stimuli. The mean withdrawal threshold in the injured paw was halved compared with that measured in the hind paw of sham rats (302.5 ± 29.7 g vs. 610.0 ± 18.5 g; Student's t-test: P < 0.01). Under these experimental conditions, oral CR4056 (range 1–10 mg·kg−1) significantly [RM two-way anova: F(3, 20) = 13.99; P < 0.0001] and dose-dependently reversed the established hyperalgesia (ED50 = 1.63 mg·kg−1; 95% CI = 1.07–2.47) (Figure 1A). Oral naproxen (30 mg·kg−1), previously reported to be poorly active in reducing postoperative pain (Whiteside et al., 2004), did not show significant effects at any time point analysed. Conversely, subcutaneous morphine (range 0.5–6 mg·kg−1) significantly [RM two-way anova: F(4, 25) = 14.40; P < 0.0001) and dose-dependently reversed the established hyperalgesia (ED50 = 1.27 mg·kg−1; 95% CI = 0.93–1.73) (Figure 1B).


Modulation of imidazoline I2 binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats.

Lanza M, Ferrari F, Menghetti I, Tremolada D, Caselli G - Br. J. Pharmacol. (2014)

(A) Anti-hyperalgesic effect of CR4056 on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). CR4056 was orally administered 24 h after surgery. Naproxen (30 mg·kg−1; oral) was used as comparison. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group). (B) Anti-hyperalgesic effects of morphine on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). Morphine was subcutaneously administered 24 h after surgery. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128066&req=5

fig01: (A) Anti-hyperalgesic effect of CR4056 on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). CR4056 was orally administered 24 h after surgery. Naproxen (30 mg·kg−1; oral) was used as comparison. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group). (B) Anti-hyperalgesic effects of morphine on postoperative pain-induced mechanical hyperalgesia in male rats (Randall-Selitto test). Morphine was subcutaneously administered 24 h after surgery. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
Mentions: Twenty-four hours after surgery, male rats showed hyperalgesia to mechanical stimuli. The mean withdrawal threshold in the injured paw was halved compared with that measured in the hind paw of sham rats (302.5 ± 29.7 g vs. 610.0 ± 18.5 g; Student's t-test: P < 0.01). Under these experimental conditions, oral CR4056 (range 1–10 mg·kg−1) significantly [RM two-way anova: F(3, 20) = 13.99; P < 0.0001] and dose-dependently reversed the established hyperalgesia (ED50 = 1.63 mg·kg−1; 95% CI = 1.07–2.47) (Figure 1A). Oral naproxen (30 mg·kg−1), previously reported to be poorly active in reducing postoperative pain (Whiteside et al., 2004), did not show significant effects at any time point analysed. Conversely, subcutaneous morphine (range 0.5–6 mg·kg−1) significantly [RM two-way anova: F(4, 25) = 14.40; P < 0.0001) and dose-dependently reversed the established hyperalgesia (ED50 = 1.27 mg·kg−1; 95% CI = 0.93–1.73) (Figure 1B).

Bottom Line: Analgesic effects of CR4056 were completely suppressed by the non-selective imidazoline I2 /α2 -adrenoceptor antagonist idazoxan, were partially reduced (~30%; P < 0.05) by the selective α2 -adrenoceptor antagonist yohimbine, but were not influenced by the non-selective I1 /α2 -adrenoceptor antagonist efaroxan or by the μ opioid receptor antagonist naloxone.When CR4056 and morphine were combined, their median effective doses were lower than expected for additive effects, both in males and in females.CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof-of-concept study in patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Rottapharm Biotech S.r.l., Monza, MB, Italy.

No MeSH data available.


Related in: MedlinePlus