Characterization of the antinociceptive effects of oxycodone in diabetic mice

Abstract

We investigated the antinociceptive efficacy of systemic and centrally injected oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Oral (p.o.) and i.t., but not i.c.v., administration of oxycodone prolonged the tail-flick latency in diabetic mice to a level that was considerably longer than the baseline latency in non-diabetic mice. However, morphine did not significantly inhibit the tail-flick response in diabetic mice. The antinociceptive effect of either p.o. or i.t. oxycodone in non-diabetic mice, but not in diabetic mice, was antagonized by pretreatment with a selective μ-opioid receptor antagonist, β-funaltrexamine. In non-diabetic mice, pretreatment with a selective κ-opioid receptor antagonist, nor-binaltorphimine, had no effect on the peak antinociceptive effect of either p.o. or i.t. oxycodone at 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception at 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the antinociceptive effects of both p.o.- and i.t.-administered oxycodone in diabetic mice. Naltrindole, a selective δ-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in either non-diabetic or diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by spinal κ-opioid receptors in diabetic mice, whereas it may interact primarily with supraspinal and spinal μ-opioid receptors in non-diabetic mice.

Introduction

Diabetic neuropathy is one of the most common late complications of diabetes mellitus and is frequently painful, with the pain involving predominantly the distal extremities (Simon and Dewey, 1981, Brown and Asbury, 1984, Boulton et al., 1998). Neuropathic symptoms usually begin with tingling or burning sensations, particularly in the calves, ankles, and feet. Pain associated with diabetic neuropathy can occur either spontaneously or as a result of exposure to only mildly painful stimuli (hyperalgesia) or to stimuli not normally perceived as painful (allodynia). Although μ-opioids have been widely used to treat patients with acute and chronic pain, they are often ineffective in the treatment of diabetic neuropathic pain (Wright, 1994, Boulton et al., 1998). In this regard, we previously reported that the antinociceptive effects of the i.c.v. administration of μ-opioid receptor agonists, such as morphine, [D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin (DAMGO) and endomorphin-2, in diabetic mice were less than those in non-diabetic mice (Kamei et al., 1992a, Kamei et al., 1992b, Kamei et al., 1994a, Kamei et al., 2000, Ohsawa and Kamei, 1997). On the other hand, we also reported that the antinociceptive effects of i.c.v. administration of δ-opioid receptor agonists, such as [D-Pen²,D-Pen⁵]enkephalin (DPDPE) and (±)TAN-67 in diabetic mice were markedly greater than those in non-diabetic mice (Kamei et al., 1994b, Kamei et al., 1995a, Kamei et al., 1997). Furthermore, we reported that the antinociceptive potency of s.c.-administered κ-opioid receptor agonist, U-50,488H, was not significantly reduced in diabetic mice compared to its effects in non-diabetic mice (Kamei et al., 1992a), or was even enhanced in diabetic mice relative to non-diabetic mice (Suzuki et al., 2001). Based on these results, we concluded that diabetic mice were selectively hypo-responsive to the antinociceptive effect mediated by μ-opioid receptor, but were sufficiently sensitive to the antinociceptive effects mediated by δ- and/or κ-opioid receptors.

Oxycodone is a semi-synthetic opioid analgesic derived from a naturally occurring alkaloid, thebaine. In humans, oxycodone has been shown to have an analgesic potency 0.7 times that of morphine after i.v. administration (Beaver et al., 1978, Kalso et al., 1990), but has been to shown to have an analgesic potency 1.5 times that of morphine after p.o. administration. It has been used clinically for over 80 years, but its pharmacology has been studied only recently. While it is known to be a μ-opioid receptor agonist, Ross and Smith (1997) reported that the antinociceptive effects of oxycodone are induced by putative κ-opioid receptors, in contrast to morphine, since oxycodone's antinociceptive effects were markedly attenuated by i.c.v. administration of nor-binaltorphimine, a selective κ-opioid receptor antagonist, but not by the i.c.v. administration of naloxonazine, a μ₁-selective opioid receptor antagonist, or naltrindole, a δ-selective opioid receptor antagonist. Furthermore, we previously reported that the antinociceptive effects of s.c. oxycodone are mainly mediated by κ-opioid receptors in diabetic mice, whereas it may interact primarily with μ-opioid receptors and partially with κ-opioid receptors in non-diabetic mice (Nozaki et al., 2005). However, the mechanisms of the oxycodone-induced inhibition of painful diabetic neuropathy are still unknown. In the present study, we examined the antinociceptive effects of systemic (p.o.) and central (i.t. and i.c.v.) administration of oxycodone in diabetic mice.