Estrogen facilitates and the kappa and mu opioid receptors mediate antinociception produced by intrathecal (-)-pentazocine in female rats

Abstract

Pentazocine, a mixed-action kappa opioid receptor (KOR) agonist, has high affinity for both KOR and the mu opioid receptor (MOR), and has been shown clinically to alleviate pain with a pronounced effect in women. However, whether local application of pentazocine in the spinal cord produces antinociception and the contribution of spinal KOR and MOR in mediating the effect of pentazocine in female rats remain unknown. Also, it is not known whether pentazocine-induced antinociception in females is estrogen-dependent. Hence, we investigated whether intrathecal (i.t.) (-)-pentazocine produces thermal antinociception and whether estrogen modulates the drug effect in female rats. Only the highest dose of pentazocine (500 nmol) was effective in producing antinociception in ovariectomized (OVX) rats. In contrast, pentazocine produced antinociception in estradiol-treated ovariectomized females (OVX+E) rats with the lowest effective dose being 250nmol. KOR or MOR mediated the effect of the lowest effective dose in OVX+E rats; however, MOR blockade extended the KOR-mediated effect of 500nmol pentazocine in both groups. In normally cycling females, the 250nmol dose was effective in producing antinociception at the proestrous, but not at the diestrous stage of the estrous cycle. Thus, estrogen facilitates and KOR or MOR mediates. the antinociceptive effect of i.t. (-)-pentazocine in female rats. Selective doses of (-)-pentazocine, with or without MOR blockade, may have a therapeutic benefit.

Keywords: Analgesia; Estrogen; Kappa opioid receptor (KOR); Mixed-action kappa opioid agonist; Mu opioid receptor (MOR); Spinal cord.

Fig. 1

In OVX rats, intrathecally administered pentazocine produced thermal antinociception. Only the 500 nmol dose was effective in increasing TFL between 5–60 minutes relative to the vehicle-treated group. Number of animals per group: 500 nmol=6, 250 nmol=9, 187.5 nmol=6, 125 nmol=7, vehicle=5.

Fig. 2

Pentazocine produced antinociception in estradiol-treated ovariectomized (OVX+E) rats. 250 and 500 nmol doses significantly increased TFL from 5–45 minutes in comparison to the vehicle-treated group. Number of animals per group: 500 nmol=6, 250 nmol=12, 187.5 nmol=7, 125 nmol=6, vehicle=6.

Fig. 3

Estrogen facilitates the antinociceptive effect produced by 250 nmol pentazocine in normally cycling females. Pentazocine significantly increased the TFL from 5 to 50 minutes in only proestrous females, but not in diestrous animals. Number of animals per group: proestrous-pentazocine=3, diestrous-pentazocine=3, proestrous-vehicle=3, diestrous-vehicle=5.

Fig. 4

The thermal antinociceptive effect of the lowest effective dose of pentazocine is mediated by KOR or MOR in OVX+E rats. The significant increase in TFL by 250 nmol pentazocine in OVX+E rats was blocked by either nor-BNI or CTAP pretreatment. Dotted lines indicate replotted data from Fig. 1 for clarity. Number of animals per group: pentazocine=12, pentazocine+CTAP=3, pentazocine+nor-BNI=5.

Fig. 5

The KOR-mediated thermal antinociceptive effect of 500 nmol pentazocine was prolonged following MOR blockade in OVX rats. Antinociception produced by 500 nmol pentazocine was blocked by a KOR antagonist, nor-BNI; however, this effect was significantly prolonged by a MOR antagonist, CTAP. Number of animals per group: pentazocine=6, pentazocine+CTAP=3, pentazocine+nor-BNI=3, vehicle+CTAP=3, vehicle+nor-BNI=3.

Fig. 6

Pretreatment with CTAP increased the duration of the antinociceptive effect of 500 nmol pentazocine in OVX+E rats. The antinociceptive effect of 500 nmol pentazocine was mediated by KOR. Number of animals per group: pentazocine=6, pentazocine+CTAP=6, pentazocine+nor-BNI=6, vehicle+CTAP=3, vehicle+nor-BNI=3.