Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain

Abstract

Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) and DPDPE ([D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [(3)H]bremazocine binding, suggesting the notion that oxycodone is a kappa(2b)-opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for mu-opioid receptors.

Safety of opioid patch initiation in Australian residential aged care

“…One explanation of this difference is that, in animal studies at least, oxycodone is thought to act as a kappa-receptor agonist (Nielsen et al, 2007) and these receptors may play an important role in the mediation of visceral pain (Staahl et al, 2006).…”

The Role of Delta Opioid Receptors in Ethanol Consumption and Seeking: Implications for New Treatments for Alcohol Use Disorders

“…Although opioid receptor agonists with highest affinity for the MOP-R, such as morphine and methadone, have been widely used in the clinic for the treatment of pain (Nissen et al, 2001;Peng et al, 2008), preclinical studies have also demonstrated that KOP-R and DOP-R both play roles in analgesia. The administration of opioid agonists acting at the KOP-R (Leighton et al, 1988;Nielsen et al, 2007;Ross & Smith, 1997;Tiseo et al, 1988) and DOP-R (Kamei et al, 1994;Kamei et al, 1997;Scherrer et al, 2004) produce analgesia and anti-allodynia in rats and mice. Furthermore, co-administration of morphine with a KOP-R or a DOP-R agonist results in enhanced analgesia (Ross et al, 2000;Suzuki et al, 1995).…”

Morfin eller oksykodon tabletter mot smerter?

“…Eksperimentelle dyrestudier har gitt opphav til spekulasjoner om at oksykodon og morfin har ulike virkningsmekanismer, og at oksykodon skulle vaere bedre egnet enn morfin i behandlingen av nevropatisk smerte (18). Imidlertid er det stor forskjell på eksperimentelle smertemodeller med gnagere og pasienter med nevropatisk smerte.…”