Ahmet Ulugol

Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats

Recent observations suggest the involvement of adenosine in the peripheral antinociceptive effect of amitriptyline in nerve-injury-induced neuropathic pain. The aim of the present investigation was to evaluate, firstly, the peripheral and systemic effects of amitriptyline on tactile allodynia in the streptozotocin (STZ)-induced diabetic rat model of neuropathic pain and, secondly, whether caffeine coadministration affects the actions of amitriptyline. Diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (50 mg/kg), and tactile allodynia was detected by application of von Frey filaments to the ventral surface of the hindpaw. Both systemic (0.5-2.0 mg/kg, i.p.) and peripheral (10-100 nmol, subcutaneously (s.c.)) administration of amitriptyline were found to produce increases in paw withdrawal thresholds, at higher doses. Coadministration of caffeine (5 mg/kg, i.p.; 1500 nmol, s.c.), at doses which produced no effect on its own, partially reversed systemic and local anti-allodynic effects of amitriptyline. These results indicate an anti-allodynic effect of both peripheral and systemic amitriptyline, and suggest the involvement of endogenous adenosine in the action of amitriptyline in this rat model of painful diabetic neuropathy. These data also suggest that topical application of tricyclic antidepressants may be useful in treating neuropathic pain in diabetics.

The Additive Antinociceptive Interaction Between WIN 55,212-2, a Cannabinoid Agonist, and Ketorolac

Combinations of nonsteroidal antiinflammatory drugs (NSAIDs) and opioids are widespread in the management of pain, allowing better analgesia with reduced side effects. Cannabinoids are promising analgesic drugs that have pharmacological properties similar to those of opioids. However, the beneficial effects of cannabinoids for pain treatment are counterbalanced by their psychotomimetic side effects. We designed the present study to evaluate the antinociceptive interaction between cannabinoids and NSAIDs in mice, using the acetic acid-induced writhing test and tail-flick test. Interactions were analyzed using isobolographic analysis. WIN 55,212-2, a cannabinoid agonist, and the NSAID ketorolac, either alone or in combination, produced dose-dependent antinociception in the writhing test. Isobolographic analysis showed additive interactions between WIN 55,212-2 and ketorolac when they were coadministered systemically. Ketorolac is inactive in the radiant heat tail-flick test in which WIN 55,212-2 was active. Ketorolac did not influence WIN 55,212-2–induced antinociception in the tail-flick test. This study demonstrated an additive antinociceptive interaction between WIN 55,212-2 and ketorolac in an inflammatory visceral pain model. The combination of cannabinoids and NSAIDs may have utility in the pharmacotherapy of pain.

Systemic agmatine attenuates tactile allodynia in two experimental neuropathic pain models in rats.

Recent evidence suggests that agmatine, an endogenous polyamine metabolite, might be an important neurotransmitter in central nervous system and has potential as a treatment of pain. The aim of our study was to evaluate the effect of agmatine on allodynia in two experimental neuropathic pain models, the spinal nerve ligation (SNL) model and the streptozocin (STZ)-induced diabetic neuropathy in rats, and to determine if the N-methyl-D-aspartate (NMDA) receptor antagonists and the nitric oxide synthase (NOS) inhibitors influence this effect of agmatine. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves, and diabetic neuropathy is induced with the injection of a single dose of STZ; these procedures resulted in tactile allodynia in the hindpaw. Tactile allodynia was detected by application of von Frey filaments to the plantar surface of the foot. Agmatine reduced mechanical allodynia with its higher doses. Dizocilpine maleate (MK-801), a NMDA receptor antagonist, and the NOS inhibitors, N(G)-nitro-L-arginine methyl ester and 7-nitroindazole, did not influence the antiallodynic effect of agmatine. These results suggest that agmatine has an antiallodynic effect in both spinal nerve ligation and diabetic models and may be a promising drug in the treatment of neuropathic pain.

Anti-allodynic and anti-hyperalgesic effects of ceftriaxone in streptozocin-induced diabetic rats☆

Glutamate is the principal excitatory neurotransmitter in the central nervous system. Recent evidence suggests that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Moreover, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids, and reduce visceral and nerve injury-induced neuropathic nociceptive responses. The aim of this study is to observe the effect of a beta lactam antibiotic, ceftriaxone, on mechanical allodynia and mechanical hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindpaws. Mechanical allodynia was detected with an electronic aesthesiometer, and mechanical hyperalgesia was studied using the method of Randall-Selitto. With its higher doses, ceftriaxone (100, 200 mg/kg, i.p.) reduced both mechanical allodynia and hyperalgesia. Dihydrokainic acid (10 mg/kg, i.p.), a selective GLT-1 transporter inhibitor, reversed the anti-allodynic and anti-hyperalgesic effects of ceftriaxone, at doses that produced no effect on its own. Our results indicate that ceftriaxone exerts an antinociceptive effect in streptozocin-induced diabetic rats and GLT-1 activation by beta lactam antibiotics may be a promising option in the treatment of diabetic neuropathy.

The behavioral effects of MK-801 injected into nucleus accumbens and caudate-putamen of rats

In this study, we investigated the behavioral effects of MK-801 (1-20 micrograms) injected into the posterior parts of nucleus accumbens (ACC) and caudate-putamen (CP) in rats. Interactions of diazepam (DZP, 10 micrograms), haloperidol (HPD, 2 micrograms), and scopolamine (SCOP, 10 micrograms) with 20 micrograms of MK-801 were also studied. All injections were done in 2 microliters. In ACC, MK-801 increased locomotion, rearing, and head shakes. The effect of MK-801 especially at 20 micrograms was accompanied by a motor syndrome: head weaves, circling, body rolls, and ataxia. DZP nonsignificantly reduced the locomotion but it significantly (p < 0.05) reduced head shakes, weaves, circling, and body rolls produced by MK-801. HPD reduced grooming and head shakes. SCOP potentiated MK-801 hyperlocomotion, whereas it decreased body rolls, head shakes, and weaves. In CP, MK-801 increased locomotion, but less than in ACC (p < 0.05). The effect of MK-801 was significantly increased by SCOP. MK-801 also increased grooming (reduced by HPD and increased by SCOP) and at 5-20 micrograms induced oral movements that were decreased by HPD. These results indicate that the posterior part of ACC is involved in MK-801 hyperlocomotion and motor syndromes, whereas CP is involved in mediating grooming and oral movements. Blockade of the muscarinic cholinergic receptors seems to facilitate hyperlocomotion and decrease head shakes produced by MK-801. Mechanisms influenced by DZP and HPD appear to be involved in motor syndrome and oral movement, respectively, induced by MK-801, but not in hyperlocomotion.

Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception

Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory CB1 receptors. The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia. In this review, we will firstly provide a background, brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia. We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception. This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation.

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice.

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.

Combined systemic administration of morphine and magnesium sulfate attenuates pain-related behavior in mononeuropathic rats

The response to opioids is reduced in neuropathic pain states. We examined the effect of the combination of morphine (0.1 mg/kg) and magnesium sulfate (125 mg/kg) on behavioral signs of neuropathic pain in spinal nerve ligated rats. Administered alone, neither drug produced any effect, but the combination exerted a significant anti-allodynic effect, which was partially reversed by naloxone. These results suggest that combining low doses of magnesium sulfate with opiates might be an alternative in treating neuropathic pain, with reduced risk of side effects.

Role of GLT-1 transporter activation in prevention of cannabinoid tolerance by the beta-lactam antibiotic, ceftriaxone, in mice

Recently, it has been indicated that beta lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Furthermore, these antibiotics have been shown to prevent the development of tolerance and dependence to opioids. Since cannabinoid tolerance is known to be similar to opioids, our purpose was to examine the effect of ceftriaxone on the development of tolerance to WIN 55,212-2, a cannabinoid agonist. The tail flick test, a rectal thermometer, and the ring test were used for evaluating the degree of tolerance to the analgesic, hypothermic, and cataleptic effects of WIN 55,212-2, respectively. Within one week, animals became completely tolerant to analgesic, hypothermic and cataleptic effects of WIN 55,212-2 (6mg/kg). Ceftriaxone, with its higher doses (100-200mg/kg), attenuated the development of tolerance to the analgesic and hypothermic effects of WIN 55,212-2, but had no effect on its cataleptic action. Dihydrokainic acid (10mg/kg), a GLT-1 transporter inhibitor, prevented this effect of ceftriaxone. Our results suggest that repeated treatment with ceftriaxone prevents the development of tolerance to the analgesic and hypothermic effects of cannabinoids, and GLT-1 activation appears to play a key role in this preventive effect of beta-lactam antibiotics.

The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.