Contralateral but not systemic administration of the kappa-opioid agonist U-50,488H induces anti-nociception in acute hindpaw inflammation in rats

Abstract

1. The anti-nociceptive effects of contralateral administration of kappa-opioid agonist U-50,488H were investigated in rats. 2. Inflammation was induced by unilateral injection of 1% carrageenan into the right hindpaw. Prior to carrageenan injection, U-50,488H or saline was administered into the left hindpaw. Withdrawal responses to mechanical and heat stimulation and oedema levels were evaluated at 3, 6 and 24 h post-carrageenan injection. 3. The results showed that the inflammatory effect of 1% carrageenan peaked after 6 h with bilateral decreases in withdrawal latencies and ipsilateral oedema formation. 4. Contralateral treatment with 0.01, 0.05, 0.3 and 2 mg of U-50,488H attenuated nociceptive reflexes to mechanical stimulation on the inflamed side at 6 h. The anti-nociceptive effect of contralateral treatment was dose-dependent at 3 and 24 h. The hindpaw withdrawal latencies to heat stimulation were prolonged at 3 and 24 h after contralateral treatment with 0.3 mg U-50,488H. No effect on inflammatory oedema formation was observed, except for a decrease at 3 h after treatment with 2 mg of U-50,488H. 5. Sciatic nerve denervation on the contralateral side abolished the anti-nociceptive effects of U-50,488H (0.3 and 2 mg). In contrast, contralateral injection of 1 mg morphine prolonged paw latencies in denervated rats. 6. Both co-administration of the peripherally selective opioid antagonist naloxone methiodide with 0.3 mg U-50,488H, and alternatively, systemic administration of 0.3 mg U-50,488H reversed the anti-nociceptive effects induced by contralateral injection of U-50,488H. 7. Taken together, our findings indicate that the contralateral administration of U-50,488H attenuates nociceptive behaviour resulting from acute inflammation. The effect is mediated via peripheral neuronal kappa-opioid receptors and, possibly, spinal cord mechanisms, suggesting a new treatment approach for acute inflammatory conditions.

Figure 1

Dose effect of contralateral treatment with U-50,488H at 3, 6 and 24 h after carrageenan injection. Changes in HWL to mechanical stimulation of the right hindpaw injected with carrageenan are shown. The left hindpaw was treated with increasing doses of U-50,488H. Data are presented as percentage (%) changes and expressed in mean±s.e.mean (vertical axis). Horizontal axis indicates U-50,488H doses presented in logarithmic scale. Significant differences are denoted as (*) 0.3 and 2 mg of U-50,488H versus 0.01 and 0.05 mg at 3 and 6 h and (+) 0.3 and 2 mg of U-50,488H versus 0.01 mg at 24 h. Student's t-test. n=8−10. ^* and+P<0.05.

Figure 2

Effect of the left sciatic nerve denervation on the contralateral treatment with U-50,488H. Changes in HWLs to mechanical (A) and thermal (B) stimulation and volume (C) of the right hindpaw injected with carrageenan are shown. The left hindpaw was given either saline, or 0.3 or 2 mg of U-50,488H (U-50) or 1 mg of morphine. Data are presented as percentage (%) changes and expressed in mean±s.e.mean (vertical axis). Horizontal axis indicates hours (h) following injection. Significant differences are denoted as (*) morphine versus saline and (+) 2 mg of U-50,488H versus saline, 0.3 mg of U-50,488H and morphine. ANOVA and Student's t-test. n=8 – 10. ^* and+P<0.05; ++P<0.01; ^***P<0.001.

Figure 3

Changes in HWLs to mechanical (A) and thermal (B) stimulation and hindpaw volume (C) of the right hindpaw injected with carrageenan. The left hindpaw was injected with either saline, 0.3 mg of U-50,488H alone (U-50 contra) or equimolar concentrations of U-50,488H and naloxone methiodide (U-50+nalox). In systemic treatment, 0.3 mg of U-50,488H was injected subcutaneously (U-50 s.c.). Data are presented as percentage changes (%) and expressed in mean±s.e.mean (vertical axis). Horizontal axis indicates hours following injection. Significant differences are denoted as (*) contralateral U-50,488H versus systemic and (+) contralateral U-50,488H alone versus together with naloxone methiodide. Student's t-test. n=8 – 10. ^** and ++P<0.01; ^*** and +++P<0.001.