Subcutaneously administered noroxymorphone was found to be inactive in all models of nociception (Figs. 2a–c) and inflammation (Fig. 3) studied, whereas a potent antinociceptive effect was observed after subcutaneous administration of oxycodone 2.5 mg/kg. No change in motor function or any signs of sedation were seen after subcutaneous administration of noroxymorphone at doses of 5, 10, and 25 mg/kg (Fig. 4). A moderate, but statistically significant, decrease in survival on the rotating rod compared with the saline group was observed after subcutaneous administration of 5 mg/kg oxycodone, as a sign of sedation and reduced motor performance. No changes in the rotarod latencies were observed with 2.5 mg/kg oxycodone (Fig. 4). Plasma concentrations of noroxymorphone have been reported to be relatively high after oral administration of oxycodone in humans and after intragastric administration in rats.9 In the same study, Lalovic et al. also found that the brain-to-plasma distribution ratio of noroxymorphone (≈0.008) is extremely low, possibly due to its markedly lower calculated logD (pH, 7–8) compared with that of oxycodone (≈2.07). This is in agreement with the present results, as noroxymorphone was found to be inactive after subcutaneous administration.
To test the possibility that noroxymorphone could activate peripheral μ-opioid receptors in inflammation, subcutaneous noroxymorphone was studied in the carrageenan model.14 However, no antihyperalgesic effect was seen. This may have been due to the relatively acute character of the carrageenan model. Carrageenan-induced inflammation has been reported to up-regulate levels of μ-opioid receptor protein in dorsal root ganglions.15 Marked up-regulation takes place after 1–3 days of carrageenan injection. A rapid induction of μ-opioid receptor protein in the dorsal root ganglions has also been reported after injection of complete Freunds’ adjuvant.16 The early phase of hyperalgesia takes place after 1–2 h of injection and the late phase after 4 days. This indicates that different models of inflammation are able to induce different kinds of changes in gene regulation in dorsal root ganglions. In the present study, for ethical reasons, the animals were tested only after 120 min of carrageenan injection. Previously, loperamide, another μ-opioid receptor agonist that does not cross the blood–brain barrier, has been shown to have antihyperalgesic effects in thermal injury17 and in arthritic rats.18 Noroxymorphone should be tested in these models at different doses to explore its possible peripheral antinociceptive effects.
Opioids are administered intrathecally to achieve segmental spinal analgesia and to avoid adverse effects mediated by supraspinal opioid-receptor activation. After intrathecal administration, the antinociceptive potencies of opioids cannot be fully predicted by the receptor binding affinity, because the pharmacological activity is modulated by complicated pharmacokinetics. Intrathecally administered opioids can spread through various routes, which are controlled mainly by their lipophilicity. Sufentanil and fentanyl have superior binding affinity for μ-opioid receptors compared with morphine.19 Both sufentanil and fentanyl are more hydrophobic (higher logD-values) compared with morphine and other opioids used in this study (Table 1). After systemic administration, sufentanil and fentanyl are more potent compared with morphine in rodents,20,21 but after intrathecal administration, the relative potencies of sufentanil and fentanyl are decreased compared with morphine.20 Buerkle and Yaksh reported that remifentanil (which is more hydrophobic compared with morphine) was 60 times more potent compared with morphine after intraperitoneal administration but only 17 times more potent compared with morphine after intrathecal administration in rats.22 These observations can be understood by the results of Ummenhofer et al. who demonstrated that after intrathecal administration of morphine a higher spinal cord exposure (peak concentration and duration) was observed compared with intrathecally administered sufentanil and fentanyl in pigs.23 Also, morphine produces longer-lasting antinociception compared with more hydrophobic opioids after intrathecal administration,24 due to slower distribution of morphine to lipid-rich tissues and vasculature compared with hydrophobic opioids. More hydrophobic molecules (high logD values) undergo rapid penetration to the lipid-rich tissues surrounding the intrathecal space.23 This can be observed as a fast onset of the analgesic effect of hydrophobic opioids (e.g., sufentanil and fentanyl) after intrathecal administration, followed by rapid vascular absorption, leading to shorter duration of analgesia compared with the more hydrophilic opioids.24 Thus, the physicochemical properties of opioids, particularly the logD, can change the relative intrathecal/systemic potencies of the drugs and, more importantly, the duration of spinal analgesia.
After intrathecal administration, drugs do not need to penetrate the lipid-rich blood–brain barrier. This enables opioids that have low logD values (better distribution in aqueous phase/higher polarity/more water soluble) to induce analgesia after intrathecal administration (Table 1). In the present study, noroxymorphone (1 and 5 μg/10 μL) induced a potent and longer-lasting antinociceptive effect compared with morphine (1 and 5 μg/10 μL) and oxycodone (200 μg/10 μL) after intrathecal administration in rats (Figs. 5a and b, and 8). McQuay et al. have postulated that the antinociceptive potencies of intrathecally administered μ-opioid receptor agonists are inversely related to their lipophilicity.25 The longer duration of the analgesic effect induced by intrathecal administration of noroxymorphone compared with oxycodone may thus be related to its lower logD value (more water soluble), because of the low vascular absorption of high-polarity drugs (like noroxymorphone) from the spinal fluid.26 The poor intrathecal potency of oxycodone compared with noroxymorphone and morphine can partly be explained by the lower μ-opioid receptor affinity of oxycodone compared with the other study drugs. The ability of oxycodone to activate μ-opioid receptor-mediated G proteins at the spinal level has been shown to be significantly weaker compared with morphine.27 Oxycodone had the highest logD value of the study drugs, indicating highest lipophilicity of the drugs studied (Table 1). According to Poyhia et al. the physicochemical properties, liposolubility, and protein-binding of oxycodone resemble those of morphine.28 The longer duration of antinociception of noroxymorphone compared with morphine seems to be related to both its chemical properties as a very hydrophilic compound with a low ClogD value (more water soluble) and its relatively high affinity to the μ-opioid receptor.9 As ED50 values were not determined, it is possible that noroxymorphone was also somewhat more potent compared with morphine in the doses used. We used similar intrathecal doses of morphine and noroxymorphone that produced similar MPE% values. However, the MPE% values were close to the maximum, even with the lower dose of 1 mg/10 mL. Compared with the study drugs, sufentanil and fentanyl have higher ClogD values (more hydrophobic drugs) (Table 1).29 When hydrophilic drugs are administered intrathecally they can spread to supraspinal parts of the central nervous system and cause sedation and respiratory depression. No respiratory depression was observed after intrathecal administration of noroxymorphone in the doses that were used in this study.
The good systemic potency of oxycodone compared with the low potency after epidural administration in humans30,31 and intrathecal administration in rats32,33 has led to the suggestion that active metabolites may be important. Lalovic et al. postulated that the analgesic activity of oxycodone can be explained by activity of its own.9 According to the results of the present study, noroxymorphone cannot explain the pharmacokinetic/ pharmacodynamic discrepancy between the good systemic effectiveness of oxycodone compared with its relatively low binding affinity to the μ-opioid receptor in vitro,9,34,35 because noroxymorphone is not pharmacologically active after subcutaneous administration in doses comparable to those produced by metabolism of oxycodone.
Mechanisms that may influence the pharmacokinetics of intrathecally administered opioids include cell membrane-bound proteins that may act as influx or eflux transporters for opioids. A recent study reported that oxycodone has a three-times higher unbound concentration in the brain than in the blood, indicating an active influx across the blood–brain barrier with an unidentified carrier protein in rats.36 P-glycoprotein plays an important role as an eflux transporter located in the blood–brain barrier.37 P-glycoprotein can limit the entry of drugs from plasma to the central nervous system. Some opioids, such as morphine and methadone, have been identified to act as substrates for P-glycoprotein.38 Conflicting results have been reported regarding the interaction of oxycodone with P-glycoprotein in rats.39,40 High concentrations of free oxycodone in the central nervous system after systemic administration may explain the high potency of systemic oxycodone.36
In rats and mice, intrathecally administered large doses of morphine may cause hyperalgesia, allodynia, and agitation.11,41–43 This behavior is not reversed by opioid receptor antagonists,11,41,43 whereas it is abolished by neurokinin 143 and N-methyl-d-aspartate antagonists,44 indicating involvement of non-opioid neuronal mechanisms. Like morphine, large doses of noroxymorphone have been reported to induce spontaneous and touch-evoked agitation in rats.11 In that study, the ED40 of noroxymorphone to produce spontaneous or touch-evoked agitation was 161 and 92 μg, respectively. In the present study, no such behavior was observed with the doses studied (1 and 5 μg).
Because of the relatively invasive nature of spinal administration of opioids, an ideal molecule for spinal analgesia should have strong potency and efficacy and a long duration of the analgesic effect, and it should not be neurotoxic. In the present study, noroxymorphone was shown to be as efficient and potent as morphine, and with a significantly longer duration of analgesic effect. Noroxymorphone may be a useful new spinal analgesic for both perioperative and long-term spinal analgesia. However, a safety assessment of noroxymorphone, focusing on neurotoxicity, should be performed before the clinical effectiveness of noroxymorphone is studied.
Noroxymorphone is a promising opioid for spinal analgesia and it should be further studied.
These studies were supported by a grant of the Finnish Association for the Study of Pain and The Graduate School in Pharmaceutical Research.
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