Helena E. Makulska-Nowak

Magnesium Ions and Opioid Agonist Activity in Streptozotocin-Induced Hyperalgesia

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.

Magnesium ions and opioid agonists in vincristine-induced neuropathy

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg(2+)) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg(2+) on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.

Venlafaxine and Neuropathic Pain

The possible mechanisms involved in the antinociceptive effect of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, after a single administration and chronic treatment were investigated in a diabetic neuropathic pain (DNP) model. VFX produced a significant antihyperalgesic effect after a single and repeated administration. This effect was reversed by pretreatment with yohimbine (a relatively selective α2-adrenergic antagonist) and p-chloroamphetamine (a neurotoxin which destroys serotonergic neurons). Conversely, naloxone (a nonselective opioid antagonist) did not reverse the effect of VFX in a DNP model. It is concluded that both noradrenergic and serotonergic mechanisms participate in the antinociceptive effect of VFX in the DNP model. However, the noradrenergic mechanism probably plays a more important role.

Effects of endomorphin-2 on arterial blood pressure and pain threshold in spontaneously hypertensive rats and modification of these effects by β-funaltrexamine and nor-binaltorphimine

The effects of intracerebroventricular (icv) administration of endomorphin-2 (E2) on arterial blood pressure and pain threshold in spontaneously hypertensive rats (SHR) and modification of these effects by K [OP2] and mu [OP3] opioid receptors antagonists were investigated. Endomorphin-2 administrated icv in doses of 8, 16 and 32 mcg produced dose-dependent analgesic and hypotensive effect. In SHR decrease in blood pressure amounted 2.667, 4.0 and 6.534 kPa, respectively. Pain threshold increased by 1.7, 3.6 and 8.9 (g x 10). In Wistar Kyoto (WKY) strain, being the normotensive controls, E2 in doses of 8 and 16 mcg decrease in blood pressure was less pronounced and amounted 1.200 and 1.467 kPa, respectively, whereas the pain threshold increased by 7.2 and 10.4 (g x 10), respectively. Both E2 effects were antagonized by equimolar icv doses of beta-funaltrexamine (beta-FNA). Equimolar doses of nor-binaltorphimine (nor-BNI) attenuated analgesic action of E2, but were without hypotensive action produced by E2. A strong correlation between drop in blood pressure and increase in pain threshold observed in the SHR and WKY strains after icv administration of E2, indicate close interaction between systems responsible for pain perception and blood pressure control.

Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model

BACKGROUND The purpose of this study was to investigate the influence of single or chronic (21 days) administration of the serotonin and noradrenaline reuptake inhibitor, venlafaxine, on the antinociceptive action of the opioid receptor agonist, morphine, in streptozotocin (STZ)-induced hyperalgesia. METHODS The studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli. Diabetes was induced by a single administration of STZ (40 mg/kg, im). RESULTS Venlafaxine was shown to modulate analgesic activity of morphine in STZ-induced hyperalgesia. However, whereas acute co-administration of venlafaxine increased the analgesic activity of morphine, chronic treatment with venlafaxine attenuated opioid efficacy. CONCLUSION Depending on the mode of administration (single or long-term), venlafaxine modulates analgesic activity of morphine. Further investigations are necessary to clarify the mechanisms of these interactions, which may be clinically relevant.

Bradykinin receptor antagonists and cyclooxygenase inhibitors in vincristine-and streptozotocin-induced hyperalgesia

Pain that accompanies neuropathy is difficult to treat. Analgesics administered as monotherapies possess low activities in relieving this kind of pain. The effect of the simultaneous administration of indomethacin (a preferential inhibitor of cyclooxygenase-1; COX-1) or celecoxib (a relatively selective inhibitor of cyclooxygenase-2; COX-2), with selective antagonists of bradykinin(2) (B(2)) bradykinin(1) (B(1)) receptors (HOE 140 or des-Arg(10)-HOE 140) on the alleviation of diabetic and toxic neuropathic pain was investigated. Pretreatment with indomethacin (0.1 mg/kg, sc) increased the antihyperalgesic activity of low daily doses of HOE 140 or des-Arg(10)HOE 140 (70 nmol/kg, ip) in a diabetic (streptozotocin(STZ)-induced) neuropathy/hyperalgesia experimental model. Premedication with celecoxib before HOE 140 or des-Arg(10)HOE 140 administration resulted in a gradual reduction of STZ hyperalgesia. Furthermore, on days 23-24, almost complete abolishment of STZ hyperalgesia was observed. After cessation of drug administration, hyperalgesia quickly returned to the baseline threshold. The results of this study suggest that inhibitors of cyclooxygenases can increase the antihyperalgesic activity of selective antagonists of B(2) and B(1) receptors in diabetic and toxic neuropathic pain models. These observations may be clinically relevant.

Enhancement of antinociceptive effect of morphine by antidepressants in diabetic neuropathic pain model

BACKGROUND Recent studies have shown that influence of antidepressants on analgesic action of opioids is heterogeneous. The aim of this study was to investigate the effect of acute and repeated (21 days) antidepressant (amitriptyline, moclobemide and reboxetine) treatment on the antinociceptive action of morphine, an opioid agonist, in streptozotocin (STZ)-induced neuropathic pain model. METHODS The studies were performed on the male Wistar rats. The changes in nociceptive thresholds were determined by using mechanical stimuli (the Randall-Selitto and the von Frey tests). Diabetes was induced by intramuscular administration of STZ. RESULTS In this work we report that acute as well as repeated per os administration of antidepressants (amitriptyline, moclobemide and reboxetine) significantly potentiated the antihyperalgesic effect of morphine in STZ-induced neuropathic pain model. CONCLUSION Combination therapy, such as classical antidepressants (amitriptyline, moclobemide) with opioids, or agents with noradrenaline reuptake inhibition and μ-opioid receptor activation could be a new target for research into treatment of painful diabetic neuropathy.

Modification of fentanyl analgesia by antidepressants.

Clinical practice often requires simultaneous administration of antidepressants with opioids (oncology, rheumatology). Coadministration may either attenuate or potentiate opioid analgesia. The purpose of this paper was to verify how the analgesic action of fentanyl (0.05 mg/kg) is affected by single administration as well as 4- or 21-day premedication with antidepressants characterized by various mechanisms of action. The effects of amitriptyline 3 mg/kg, moclobemide 5 mg/kg, fluoxetine 5 mg/kg and reboxetine 0.08 mg/kg were investigated. Experiments were conducted on normotensive Wistar Kyoto rats. The pain threshold was measured using an analgesimeter. It was concluded that the single administration of an antidepressant increases the analgesic action of fentanyl. Four-day premedication with fluoxetine and reboxetine significantly attenuated the antinociceptive action of fentanyl, whereas 21-day premedication with all antidepressants investigated (fluoxetine, amitriptyline, moclobemide, reboxetine) markedly decreased it. The potential clinical importance of this observation is discussed.

Influence of acute and subchronic oral administration of dehydroepiandrosterone (DHEA) on nociceptive threshold in rats

BACKGROUND Dehydroepiandrosterone (DHEA), a neurosteroid, is known to be the most abundant hormone in the human body. Its role in the central nervous system has not been well defined. Previous studies indicate that DHEA is synthesized in the spinal cord and plays an important role in pain modulation. In the present study, we investigated the effect of DHEA on pain threshold in rats after both acute and subchronic treatment. METHOD Rats were orally administered with DHEA at a dose of 10 mg/kg once daily and the pain threshold was measured with mechanical and thermal stimuli. RESULTS After acute treatment, DHEA exhibited pronociceptive effects which lasted up to 150 min. After subchronic administration, DHEA showed an opposite effect by elevating the pain threshold. CONCLUSION The results suggest that DHEA could be indicated as a drug to improve treatment of chronic pain disorders.

Paradoxical effects of intracerebroventricular low-dose opioid antagonists in SHR with chronic pain.

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.