Magnesium Ions and Opioid Agonist Activity in Streptozotocin-Induced Hyperalgesia

Abstract

Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg²⁺) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg/kg i.p.) and fentanyl (0.0625 mg/kg i.p.), as well as the partial agonist buprenorphine (0.075 mg/kg) had only little effect on streptozotocin-induced hyperalgesia. However, pretreatment with Mg²⁺ at a dose of 40 mg magnesium sulfate/kg i.p. markedly enhanced the analgesic activity of all three investigated opioids. Practical aspects of co-administration of magnesium and opioids in diabetic neuropathy are discussed.

Additive Effect of Combined Application of Magnesium and MK-801 on Analgesic Action of Morphine

“…As shown in our previous study [1], starting from day 3, a statistically significant gradual decrease in the nociceptive threshold was observed in STZ-treated animals. The decrease reached its nadir on day 7 in the Randall-Selitto test and remained on a similar level until day 40 (data not shown).…”

“…Therefore, coadministration of opioids with a compound that will increase the analgesic efficiency of these drugs, without concomitant intensification of their undesirable effects, will be of great clinical importance. As previously reported from this laboratory, magnesium administered in relatively low doses markedly potentiated opioid analgesia in neuropathic pain, in which the effectiveness of opioids is limited [1,2]. Since similar observations were also reported by other authors [3,4,5], it was of interest to further investigate the effect of magnesium ions (Mg 2+ ) on the analgesic activity of morphine as well as to compare it with the action of MK-801, a noncompetitive N-methyl- D -aspartate (NMDA) receptor antagonist.…”

“…Control animals were injected intraperitoneally with 0.9% saline (control to magnesium sulfate, morphine, MK-801) according to the same time schedule. Diabetes was induced by intramuscular administration of STZ at a dose of 40 mg/kg of body weight, as described by Nakhoda and Wong [6] and Bujalska et al [1]. …”

165 Modification of Morphine Analgesia by Venlafaxine in Diabetic Neuropathic Pain Model

“…Mechanical hyperalgesia, observed after three weeks of diabetes, showed a reduced sensitivity to morphine-induced antinociception. This is consistent with numerous earlier reports of a significant reduction in the antinociceptive potency of morphine that was associated with hyperglycemic state in diabetes [4,5,24]. Alteration in the µ-opioid receptor function, an increase in the levels of interleukin-1b, and accumulation of morphine-3-glucuronide were reported in diabetic rats [9].…”

“…The venlafaxine dose was selected based on a screening test (data not shown) and the morphine dose -as previously described [4]. Venlafaxine was administered orally (po) at 10 and 50 mg/kg doses, whereas morphine was administered subcutaneously (sc) at a 5 mg/kg dose.…”