Effects of peripheral κ opioid receptor activation on inflammatory mechanical hyperalgesia in male and female rats

Abstract

Activation of peripheral κ opioid receptors (KOR) effectively relieves pain and hyperalgesia in preclinical and clinical models of pain. Although centrally located KOR activation results in sexually dimorphic effects, it is unclear whether peripheral KOR also produces sex dependent effects in persistent inflammatory pain conditions. In this study, we investigated whether local administration of a specific KOR agonist, U50, 488 relieve mechanical hyperalgesia induced by the injection of complete Freund's adjuvant (CFA) in the rat hindpaw, and whether there are sex differences. The effects of U50, 488 were assessed three days after the induction of CFA-induced inflammation, a time point at which mechanical hyperalgesia was most prominent. There were no sex differences in baseline and CFA-induced changes in mechanical thresholds between male and female rats. Local treatment of U50, 488 produced moderate, but significant, anti-hyperalgesia in both male and female rats. However, U50, 488 was significantly more effective in male rats at the highest dose of U50, 488. We confirmed that the highest dose of U50, 488 used in this study did not produce systemic effects, and that the drug effect is receptor specific. On the basis of these results, we suggest that local KOR agonists are effective in mitigating mechanical hyperalgesia under a persistent inflammatory pain condition and that sex differences in anti-hyperalgesic effects become more evident at high doses.

Figure 1

Effects of i.pl injection of CFA on hindpaw mechanical sensitivity. (A) Baseline thresholds of CFA and ISO treated male and female rats. (B) Time course of changes in mechanical thresholds of CFA and ISO treated male and female rats. * and + indicate significant group and time effect, respectively. Each group consisted of n=6.

Figure 2

Effects of local treatment of U50, 488 on CFA-induced mechanical hyperalgesia. On day 3 of CFA injection, changes in mechanical thresholds after local U50, 488 treatment were measured for 180 minutes in male (A) and female (B) rats. The drug was administered 5 minutes after pre-treatment measurement of mechanical threshold. * indicates significant groups effect compared to PBS at p < 0.05. (C) Direct comparisons of percent changes in mechanical thresholds between male and female rats following PBS or drug treatment. * and + indicate significant group and time effect, respectively. Each group consisted of n=6.

Figure 3

Local and receptor mediated effects of U50, 488. On day 3 of CFA injection, U50, 488 injected into the hindpaw contralateral to the CFA-inflamed paw had no effect on mechanical thresholds in either males or females (A, B). On day 3 of CFA injection, changes in mechanical thresholds after local U50, 488 treatment with nor-BNI in the same paw were measured in male and female rats (C). The nor-BNI was administered 5 minutes after the pre-treatment measurement of mechanical threshold, followed by U50, 488. *, + indicates significant group and time effect, respectively. Each group consisted of n=6.