Magdalena Bujalska-Zadrożny

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.

Influence of nitric oxide synthase or cyclooxygenase inhibitors on cannabinoids activity in streptozotocin-induced neuropathy

BACKGROUND Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy. METHODS Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ. RESULTS In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241. CONCLUSIONS The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.

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.

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.

Antinociceptive properties of esculetin in non-inflammatory and inflammatory models of pain in rats

Some studies suggest that 5‐lipoxygenase (5‐LOX) inhibition or leukotriene receptor antagonism may effectively attenuate different kinds of pain. In the present study, we investigated whether esculetin (which, among other actions, potently inhibits 5‐LOX) possesses analgesic activity in acute non‐inflammatory pain and acute inflammatory pain models in rats. We also examined the effects of zileuton, a selective 5‐LOX inhibitor, on esculetin activity. Plasma concentrations of leukotriene B4 (LTB4) after administration of esculetin were also determined. Esculetin (1.25–20 mg/kg, i.p.) dose‐dependently alleviated hyperalgesia and exhibited antinociceptive effects in both experimental models. The greatest effect of esculetin was observed with a dose of 20 mg/kg. In carrageenan‐induced inflammatory pain in rats, 20 mg/kg esculetin reversed or mitigated hyperalgesia, increasing the threshold to mechanical stimuli from a control value of −23.8 ± 1.8% to 15.2 ± 2.2% (P < 0.01) and that to thermal stimuli from −52.5 ± 6.1% to −9.5 ± 3.9% (P < 0.01). In non‐inflammatory pain, after esculetin (20 mg/kg) administration the threshold values to mechanical and thermal stimuli increased to 75.9 ± 4.2% and 59.2 ± 4.3%, respectively (P < 0.01 for both). Zileuton (30 mg/kg, p.o.) alone slightly but significantly increased the pain threshold in the non‐inflammatory and inflammatory acute pain models. Pretreatment with 30 mg/kg, p.o., zileuton significantly enhanced the analgesic activity of 5 mg/kg, i.p., esculetin in both pain models. Moreover, esculetin (10 mg/kg, i.p.) decreased LTB4 concentrations in the blood from 244 ± 29 pg/mL in the control group to 185 ± 11 pg/mL (P < 0.005). The results of the present study suggest the involvement of the 5‐LOX pathway in esculetin analgesia.

Naloxone exacerbates memory impairments and depressive-like behavior after mild traumatic brain injury (mTBI) in mice with upregulated opioid system activity

HighlightsSeverity of post‐mTBI deficits correlates with endogenous opioid system activity.Increased opioid tone protects against mTBI‐induced memory deficits.Naloxone impairs memory and exacerbates depressive‐like behavior only in HA mice.mTBI strongly induces depressive‐like behavior in LA mice Abstract The neuroprotective role of the endogenous opioid system in the pathophysiological sequelae of brain injury remains largely ambiguous. Noteworthy, almost no data is available on how its genetically determined activity influences the outcome of mild traumatic brain injury. Thus, the aim of our study was to examine the effect of opioid receptor blockage on cognitive impairments produced by mild traumatic brain injury in mice selectively bred for high (HA) and low (LA) swim‐stress induced analgesia that show innate divergence in opioid system activity. Mild traumatic brain injury was induced with a weight‐drop device on anaesthetized mice. Naloxone (5 mg/kg) was intraperitoneally delivered twice a day for 7 days to non‐selectively block opioid receptors. Spatial memory performance and manifestations of depressive‐like behavior were assessed using the Morris Water Maze and tail suspension tests, respectively. Mild traumatic brain injury resulted in a significant deterioration of spatial memory performance and severity of depressive‐like behavior in the LA mouse line as opposed to HA mice. Opioid receptor blockage with naloxone unmasked cognitive deficits in HA mice but was without effect in the LA line. The results suggest a protective role of genetically predetermined enhanced opioid system activity in suppression of mild brain trauma‐induced cognitive impairments. Mice selected for high and low swim stress‐induced analgesia might therefore be a useful model to study the involvement of the opioid system in the pathophysiology and neurological outcome of traumatic brain injury.

Cannabinoid Ligands and Alcohol Addiction: A Promising Therapeutic Tool or a Humbug?

The vast therapeutic potential of cannabinoids of both synthetic and plant-derived origins currently makes these compounds the focus of a growing interest. Although cannabinoids are still illicit drugs, their possible clinical usefulness, including treatment of acute or neuropathic pain, have been suggested by several studies. In addition, some observations indicate that cannabinoid receptor antagonists may be useful for the treatment of alcohol dependence and addiction, which is a major health concern worldwide. While the synergism between alcohol and cannabinoid agonists (in various forms) creates undesirable side effects when the two are consumed together, the administration of CB1 antagonists leads to a significant reduction in alcohol consumption. Furthermore, cannabinoid antagonists also mitigate alcohol withdrawal symptoms. Herein, we present an overview of studies focusing on the effects of cannabinoid ligands (agonists and antagonists) during acute or chronic consumption of ethanol.

Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine

The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine.

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

As previously reported, magnesium ions (Mg2+) administered in relatively low doses markedly potentiated opioid analgesia in neuropathic pain, in which the effectiveness of opioids is limited. Considering that Mg2+ behaves like an N-methyl-D-aspartate receptor antagonist, the effect of this ion on the analgesic action of morphine was compared with that of MK-801. Acute pain was evoked by mechanical or thermal stimuli, whereas neuropathic hyperalgesia was induced by streptozotocin (STZ) administration. Magnesium sulphate (40 mg/kg i.p.) or MK-801 (0.05 mg/kg s.c.) administered alone did not modify the nociceptive threshold to acute stimuli or the streptozotocin hyperalgesia but significantly augmented the analgesic action of morphine (5 mg/kg i.p.). Furthermore, if these drugs (i.e. magnesium sulphate and MK-801) were applied concomitantly, a clear additive effect on the analgesic action of morphine occurred in both models of pain. Possible explanations of these observations are 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.