Comparative Pharmacological Profiles of Morphine and Oxycodone under a Neuropathic Pain-Like State in Mice: Evidence for Less Sensitivity to Morphine

Abstract

The present study was undertaken to investigate pharmacological actions induced by morphine and oxycodone under a neuropathic pain-like state. In the m-opioid receptor (MOR) binding study and G-protein activation, we confirmed that both morphine and oxycodone showed MOR agonistic activities. Mice with sciatic nerve ligation exhibited the marked neuropathic pain-like behavior. Under these conditions, antinociception induced by subcutaneously (s.c.) injected morphine was significantly decreased by sciatic nerve ligation, whereas s.c. injection of oxycodone produced a profound antinociception in sciatic nerve-ligated mice. There were no significant differences in spinal or supraspinal antinociception of morphine and oxycodone between sham operation and nerve ligation. Moreover, either morphine-or oxycodone-induced increase in guanosine-5 0 -o-(3-thio) triphosphate ([ 35 S]GTPgS) binding in the spinal cord, periaqueductal gray matter and thalamus in sciatic nerve-ligated mice was similar to that in sham-operated mice. Antinociception induced by s.c., intrathecal, or intracerebroventricular injection of the morphine metabolite morphine-6-glucuronide (M-6-G) was significantly decreased by sciatic nerve ligation. Furthermore, the increase in the G-protein activation induced by M-6-G was eliminated in sciatic nerve ligation. In addition, either morphine-or oxycodone-induced rewarding effect was dramatically suppressed under a neuropathic pain-like state. The increased [ 35 S]GTPgS binding by morphine or oxycodone was significantly lower in the lower midbrain of mice with sciatic nerve ligation compared with that in control mice. These findings provide further evidence that oxycodone shows a profound antinociceptive effect under a neuropathic pain-like state with less of a rewarding effect. Furthermore, the reduction in G-protein activation induced by M-6-G may, at least in part, contribute to the suppression of the antinociceptive effect produced by morphine under a neuropathic pain-like state.

Oxycodone-Induced Analgesic Effects in a Bone Cancer Pain Model in Mice

“…The antinociceptive effect of oxycodone on ambulatory and neuropathic pains was almost equal to that on ongoing pain, however, the antinociceptive effect of morphine on ambulatory and neuropathic pains, and that of fentanyl on ambulatory pain were different from those on ongoing pain. Oxycodone, as well as morphine and fentanyl, is a µ-opioid receptor agonist and the intrinsic activity of oxycodone to the µ-opioid receptor is weaker than that of morphine and fentanyl [3]. The different profile of each opioid on ongoing, ambulatory and neuropathic pains could not be explained by either the different binding property to the µ-opioid receptor or the different brain penetration.…”

“…Oxycodone has a high selectivity for the µ-opioid receptor with apparent agonistic activity, but the binding affinity of oxycodone to the µ-opioid receptor is weaker than that of other opioids. Specifically, the affinity of oxycodone to the µ-opioid receptor is 1/10 that of morphine [1,2,3]. Regardless of the relatively low receptor affinity, several reports have demonstrated that oxycodone induces obvious antinociception on thermal and mechanical stimuli in several animal models [4,5,6].…”

“…Regardless of the relatively low receptor affinity, several reports have demonstrated that oxycodone induces obvious antinociception on thermal and mechanical stimuli in several animal models [4,5,6]. In addition, it has been concluded that oxycodone induces antinociception via the µ-opioid receptor, since the antinociceptive effects of oxycodone were antagonized by a µ-opioid receptor antagonist [3]. …”

Morphine, Oxycodone, and Fentanyl Exhibit Different Analgesic Profiles in Mouse Pain Models

“…Furthermore, in a mouse femur bone cancer (FBC) model, which showed similar pathological symptoms to human bone metastasis, morphine and fentanyl were reported to exhibit antinociceptive effects on several pain-related behaviors (19). Although those studies showed that these opioids were effective on several different types of pain, only a few studies have directly compared the pharmacological efficacy of the three opioids in animal pain models (17). For an appropriate opioid use, it is important to understand the pharmacological profile of each opioid in various types of pain.…”

“…These opioids exhibited the significant antinociceptive effects, as measured by the tail-flick test, on pain caused by thermal stimuli (17). In the mouse sciatic nerve ligation (SNL) model, oxycodone has been shown to reverse the nociceptive pain caused by mechanical stimuli (18).…”