In a previous study that did not examine for sex differences we reported that morphine (2 mg) enhanced the analgesic effect of the agonist-antagonist κ-opioid pentazocine 14
. In the present study, we found that morphine reversed the anti-analgesic effect of nalbuphine, but that this effect was statistically significant only in males. Neither dose of morphine produced a significant effect in females.
The effect of morphine on the ability of nalbuphine to produce analgesia could be due to the summation of separate analgesic effects of morphine acting at µ-opioid receptors and nalbuphine at κ-receptors, but examination of the data does not support this explanation in the current study. While, an additive effect of morphine might be expected to be similar in both sexes, this was not the case; the effect of morphine was significant only in males. Also, with analgesic summation the higher (4 mg) dose of morphine should have produced greater enhancement than the lower (2 mg) dose, but if anything the opposite was observed. In combination with nalbuphine only the 2 mg morphine dose significantly improved the analgesic effect of nalbuphine alone in males.
An alternative explanation—one that is more consistent with the current findings—is that nalbuphine analgesia is unmasked by morphine blockade of the action of nalbuphine at an anti-analgesia receptor. Previously, we showed that the opioid receptor antagonist naloxone enhances nalbuphine analgesia in both sexes (males > females)11
, a finding that formed the basis of a two-receptor hypothesis for the effect of nalbuphine on postoperative pain 5,7,8,11
. According to this hypothesis, nalbuphine induces anti-analgesia as well as analgesia by acting at distinct “anti-analgesia” and “analgesia” opioid receptors. Thus, the effect of nalbuphine alone on pain is observed as the sum of these two opposing actions. To account for the sexually dimorphic analgesic effect of κ-opioids, the hypothesis proposes that males have more “anti-analgesia” receptors than females. The ability of naloxone to enhance κ-opioid analgesia and eliminate the sexual dimorphism results from naloxone’s greater affinity for the anti-analgesia receptor.
While nalbuphine, morphine, and naloxone all bind to µ-, δ-, and κ-opioid receptors 3,18
, the efficacy of each drug as an agonist is markedly different. Naloxone, the prototypical opioid receptor antagonist
is essentially devoid of agonist efficacy at any opioid receptor15
. The efficacy of nalbuphine is relatively low at the µ-opioid receptor, which is consistent with its ability to antagonize some actions of morphine 2,21
and still act as a low efficacy µ-agonist, for example in producing mild respiratory depression, when administered alone20
. In contrast, morphine is well known as a highly efficacious µ- opioid receptor agonist with little if any efficacy at κ-opioid receptors 16,17
If the anti-analgesia receptor is an opioid subtype, morphine, like naloxone, appears to function as an antagonist
at this receptor blocking the anti-analgesic effect of nalbuphine. However, since higher doses of morphine produce analgesia, the analgesic effect of a combination of any given pair of µ and κ opioid agonists likely depends on an array of factors, including the dose ratio of the two drugs, and their relative binding affinities for the relevant opioid receptor subtype. Different dose ratios could result in enhanced analgesia, diminished analgesia, or no change in analgesia compared to either drug alone 1,14,22
. In addition, the relatively short plasma half-lives of both morphine and naloxone imply that plasma concentrations of these drugs do not correspond well with the prolonged time course of analgesia. Future studies to address the optimal dose ratio for morphine to enhance nalbuphine analgesia in both males and females should provide useful information with respect to properties of the receptor at which drugs such as morphine and naloxone act to block nalbuphine-induced anti-analgesia.
In summary, doses of morphine well below the lowest dose that produces analgesia reversed nalbuphine-induced anti-analgesia in both females and males with postoperative pain. Further investigation is needed to determine the optimal dose ratio that provides maximum enhancement of nalbuphine analgesia in males and females. Identification of the receptor(s) at which agonist-antagonist κ-opioids act to induce anti-analgesia is important in order to understand the mechanism(s) underlying sexual dimorphism in opioid analgesia and might aid in the development of novel analgesic drugs selectively targeted at the analgesia receptors and/or antagonists selectively targeted at anti-analgesia receptors. Eliminating agonist-antagonist κ-opioid-induced anti-analgesia would not only produce greater analgesia using lower doses of opioids, but potentially also decrease side effects, including abuse liability.