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, 171 (6), 1580-90

Antihyperalgesic Effects of Imidazoline I(2) Receptor Ligands in Rat Models of Inflammatory and Neuropathic Pain

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Antihyperalgesic Effects of Imidazoline I(2) Receptor Ligands in Rat Models of Inflammatory and Neuropathic Pain

Jun-Xu Li et al. Br J Pharmacol.

Abstract

Background and purpose: A new imidazoline I2 receptor ligand, CR4056, is effective for chronic inflammatory pain and diabetic neuropathy. However, it is unclear whether other I2 receptor ligands have similar effects and whether antinociceptive tolerance develops with repeated treatment.

Experimental approach: The Von Frey filament test was used to measure mechanical hyperalgesia and the plantar test to measure thermal hyperalgesia in rats injected with complete Freund's adjuvant (CFA) treatment or had undergone surgery to induce chronic constriction injury (CCI), models of inflammatory pain and peripheral neuropathic pain respectively. The effects of morphine and I2 receptor ligands, 2-BFI, BU224, tracizoline and CR4056, 3.2-32 mg·kg(-1) , i.p., on hyperalgesia or affective pain (as measured by a place escape/avoidance paradigm) were studied in separate experiments.

Key results: Morphine and the I2 receptor ligands (2-BFI, BU224 and tracizoline) all dose-dependently attenuated mechanical and thermal hyperalgesia in CFA-treated rats. The anti-hyperalgesic effects of 2-BFI in CFA-treated and CCI rats were attenuated by the I2 receptor antagonist idazoxan. The combination of 2-BFI and morphine produced additive effects against mechanical hyperalgesia in CFA-treated rats. Repeated treatment (daily for 7-9 days) with 2-BFI or CR4056 did not produce antinociceptive tolerance in CFA-treated or CCI rats. Morphine and the I2 receptor ligands (2-BFI, BU224 and CR4056) were all effective at attenuating place escape/avoidance behaviour in CFA-treated rats.

Conclusions and implications: Imidazoline I2 receptor ligands have antihyperalgesic effects in rat models of inflammatory and neuropathic pain and may represent a new class of pharmacotherapeutics for the management of chronic pain.

Keywords: affective pain; chronic constriction injury; complete Freund's adjuvant; hyperalgesia; imidazoline I2 receptor; plantar test; von Frey test.

Figures

Figure 1
Figure 1
CFA-induced mechanical hyperalgesia (top left) and increased paw thickness (bottom left) and CCI-induced mechanical hyperalgesia (right) in rats. Ordinates: top, paw withdrawal threshold (g) measured by electronic von Frey filament (top); bottom, paw thickness (mm) measured by electronic caliper. Abscissa: days after CFA injection or CCI surgery. For filled circles, all the data points were significantly different from the data point above ‘0’ as analysed by two-way anova and post hoc Bonferroni's analysis (n = 6 per group).
Figure 2
Figure 2
Effects of morphine, 2-BFI, BU224 and tracizoline on mechanical (top) and thermal hyperalgesia (bottom) in CFA-treated rats. Left hind (non-injured) paw; right hind (CFA-treated) paw. * P < 0.05 as compared to left hind paw above ‘V’; #P < 0.05 as compared to left hind paw above ‘V’ paw (n = 6 per group).
Figure 3
Figure 3
Antihyperalgesic effects of morphine, 2-BFI, BU224 and tracizoline on mechanical (top) and thermal hyperalgesia (bottom) in CFA-treated rats. Data are expressed as percentage of maximal possible effect and plotted as a function of drug dose; 100% MPE represents data from the baseline measure of the right hind paw before CFA treatment.
Figure 4
Figure 4
Effects of idazoxan on the antihyperalgesic activity of 2-BFI in CFA-treated (left) and CCI (right) rats. See Figure 2 for other details (n = 6 per group).
Figure 5
Figure 5
Effects of 2-BFI alone and in combination with morphine on CFA-induced mechanical hyperalgesia in rats. Left: dose–effect curves for 2-BFI alone and 2-BFI/morphine under a fixed proportion of 1:1. Right: isobologram for 2-BFI/morphine mixture. Abscissa scale: ED50 value of morphine. Ordinate scale, ED50 value of 2-BFI (n = 6 per group).
Figure 6
Figure 6
Effects of daily treatment with 10 mg·kg−1 2-BFI (left) or 10 mg·kg−1 2-BFI followed by 32 mg·kg−1 CR4056 (right) on CCI-(left) or CFA-(right) induced mechanical hyperalgesia in rats. Arrow indicates the day that the animals received saline instead of treatment drug. *P < 0.05 as compared to the control. See Figure 1 for other details (n = 6 per group).
Figure 7
Figure 7
Mean percentage of time (± SEM) spent in the white side of the chamber in 5 min intervals over the 30 min session for CFA-treated rats following stimulation with a 60 g von Frey filament every 15 s. Rats were stimulated on the right paw (CFA-treated) on the black side of chamber and the left paw (untreated) on the white side of the chamber. *P < 0.05 versus saline-treated control rats.

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