ro13-9904 and Neuralgia

As an "off-target" effect, cephalosporins can enhance glutamate transporter-1 expression in astrocytes to recycle glutamate from synaptic cleft, and exhibited analgesic properties in animals and humans with chronic pain.. In the present study, we focused on making a side-by-side comparison of the analgesic potentials of cefadroxil and ceftriaxone, using rodent models of peripheral neuropathic pain, inflammatory pain and incisional pain. Microdialysis technique was adopted to validate the in vivo glutamate regulatory properties of these two drugs in central nervous system.. We have shown that cefadroxil and ceftriaxone are beneficial in a variety of pain scenarios, without inducing observable side effects. The two cephalosporins worked better on neuropathic pain, rather than inflammatory pain or incisional pain, suggesting nociceptive system was differentially affected. Further, microdialysis has confirmed that cephalosporins can effectively reverse the elevated levels of glutamate in brain of animals with neuropathic pain.. The outcome of this study may guide us to identify a molecular skeleton derived from cefadroxil, based on which we could possibly develop new non-antibiotic analgesic compounds with glutamate recycling properties.

Topics: Analgesics; Animals; Cefadroxil; Ceftriaxone; Disease Models, Animal; Glutamates; Humans; Neuralgia

Chemotherapy-induced peripheral neuropathy (CIPN) is a pharmacoresistant neurological complication induced by some antitumor drugs. This study aimed to assess antiallodynic properties of aripiprazole and ceftriaxone used alone or in combination to attenuate neuropathic pain related to CIPN caused by oxaliplatin.. Neuropathic pain was induced in mice by a single intraperitoneal dose of oxaliplatin (10 mg/kg). Aripiprazole and ceftriaxone were used in a single- or repeated dosing protocol. Their antiallodynic activity was assessed using von Frey and cold plate tests on the day of oxaliplatin injection and after 7 days. The influence of aripiprazole and ceftriaxone on animals' locomotor activity and motor coordination was also assessed.. Single-dose and repeated-dose aripiprazole 10 mg/kg and ceftriaxone 200 mg/kg used alone and in combination attenuated early-phase and late-phase tactile allodynia in oxaliplatin-treated mice. Repeated administrations of ceftriaxone 200 mg/kg prevented the development of late-phase tactile allodynia. Both drugs showed no antiallodynic properties in the cold plate test. Single-dose aripiprazole 1 and 10 mg/kg but not its repeated administration significantly decreased locomotor activity of oxaliplatin-treated mice. Single-dose aripiprazole 1 and 10 mg/kg, aripiprazole 1 mg/kg + ceftriaxone 50 mg/kg and aripiprazole 1 mg/kg + ceftriaxone 200 mg/kg impaired motor coordination in the rotarod test.. In mice, neither ceftriaxone nor aripiprazole attenuated cold allodynia. Ceftriaxone alone could attenuate tactile allodynia caused by oxaliplatin without inducing motor adverse effects. Although the administration of aripiprazole reduced tactile allodynia, this effect seems to be limited considering severe motor deficits induced by this drug.

Topics: Animals; Aripiprazole; Ceftriaxone; Drug Therapy, Combination; Hyperalgesia; Male; Mice; Neuralgia; Oxaliplatin; Pain Measurement; Pain Threshold

Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.. Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.. Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.. Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.. Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.

Topics: Analgesics; Animals; Astrocytes; Ceftriaxone; Cells, Cultured; Clavulanic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Transporter 2; Glutamic Acid; Humans; Male; Neuralgia; Pain Threshold; Rats; Rats, Sprague-Dawley; Spinal Cord; Up-Regulation

Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG-specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain.

Topics: Analgesics, Non-Narcotic; Animals; Ceftriaxone; Disease Models, Animal; Excitatory Amino Acid Transporter 2; Hot Temperature; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neuralgia; Periaqueductal Gray; Sciatic Nerve; Spinal Cord; Touch

The relation between glutamate homeostasis and PPAR gamma has got tremendous importance in nerve trauma and pain. Present study has been designed to elucidate the interaction between the GLT-1 activator (ceftriaxone) and PPAR gamma agonist (pioglitazone) in the spinal nerve ligation induced neuropathic pain.. Male SD rats were subjected to spinal nerve ligation to induce neuropathic pain. Pioglitazone, ceftriaxone and their combination treatments were given for 28 days. Various behavioral, biochemical, neuroinflammatory and apoptotic mediators were assessed subsequently.. In the present study, ligation of L5 and L6 spinal nerves resulted in marked hyperalgesia and allodynia to different mechanical and thermal stimuli. In addition there is marked increase in oxidative-nitrosative stress parameters, inflammatory and apoptotic markers in spinal cord of spinal nerve ligated rats. Treatment with pioglitazone and ceftriaxone significantly prevented these behavioral, biochemical, mitochondrial and cellular alterations in rats. Further, combination of pioglitazone (10mg/kg, ip) with ceftriaxone (100mg/kg, ip) significantly potentiated the protective effects as compared to their effects per se.. Based on these results we propose that possible interplay between the neuroprotective effects of pioglitazone and ceftriaxone exists in suppressing the behavioral, biochemical, mitochondrial, neuroinflammatory and apoptotic cascades in spinal nerve ligation induced neuropathic pain in rats.

Topics: Animals; Ceftriaxone; Disease Models, Animal; Drug Delivery Systems; Drug Therapy, Combination; Excitatory Amino Acid Transporter 2; Male; Neuralgia; Neuroprotective Agents; Pain Measurement; Pioglitazone; PPAR gamma; Rats; Rats, Sprague-Dawley; Signal Transduction; Thiazolidinediones

In our previous study, ceftriaxone, a beta-lactam antibiotic, elicited antinociceptive effects in the chronic constriction injury (CCI) of neuropathic pain. In this study, we assessed apoptosis and oxidative stress in the spinal cord of neuropathic rats treated with ceftriaxone.. 45 male Wistar rats were divided as naïve, sham, normal saline-treated CCI rats, and CCI animals treated with the effective dose of ceftriaxone. Involvement of Bax, Bcl2, and caspases 3 and 9, important contributors of programmed cell death (apoptosis), was determined using western blotting at days 3 and 7. The markers of oxidative stress including malondialdehyde (MDA) and reduced glutathione (GSH) were measured on days 3 and 7.. Increased Bax/Bcl2 ratio and cleaved active forms of caspases 3 and 9 were observed in the spinal cord of CCI rats on day 3. Ceftriaxone attenuated the increased levels of Bax and cleaved forms of caspases 3 and 9, while it increased Bcl2 levels. Bax and active forms of caspases declined by day 7. Consequently, comparison among groups showed no difference at this time. CCI enhanced MDA and decreased GSH on days 3 and 7, while ceftriaxone protected against the CCI-induced oxidative stress.. Our results suggest that ceftriaxone, an upregulator/activator of GLT1, could concomitantly reduce oxidative stress and apoptosis and producing its new analogs lacking antimicrobial activity may represent a novel approach for neuropathic pain treatment.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Apoptosis Regulatory Proteins; Ceftriaxone; Disease Models, Animal; Glutathione; Male; Malondialdehyde; Neuralgia; Oxidative Stress; Rats; Rats, Wistar; Time Factors

Peripheral neuropathy is a common adverse effect of bortezomib-based chemotherapy. In this study we have investigated the role played by subtype 5 of metabotropic receptors in bortezomib induced peripheral neuropathy. Rats were administered with bortezomib three times weekly at 0.20 mg/kg for a total of 4 weeks in presence or absence of mGluR5 antagonist MPEP. The animals were submitted to paw-pressure test and tail sensory nerve conduction measurement more times during the treatment and follow-up. Bortezomib treatment induced a progressively increasing hyperalgesia in rat which was accompanied by a significant reduction in sensory nerve conduction velocity (SNCV). MPEP prevented the emergence of bortezomib-induced pain and counteracted SNCV reduction when co-administered with bortezomib treatment. Spinal extracellular glutamate levels increased in rats treated with bortezomib. Bortezomib-induced onset of the hyperalgesia and SNCV decrease could be prevented by agents that promote the reuptake of glutamate maintaining spinal glutamate at basal level. Our data support the manipulation of the glutamatergic system through the mGluR5 receptor in bortezomib induced peripheral neuropathy. The use of antagonists at the mGluR5, initiated at the same time as bortezomib-chemotherapy, might reduce the number of patients who develop painful peripheral chemo-neuropathy.

Topics: Analgesics; Animals; Boronic Acids; Bortezomib; Ceftriaxone; Cell Line, Tumor; Cell Survival; Central Nervous System Agents; Disease Models, Animal; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Hyperalgesia; Injections, Spinal; Male; Neural Conduction; Neuralgia; Peripheral Nervous System Diseases; Pyrazines; Pyridines; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5

Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. So far, there has been insufficient data on the relationship between glutamate transporters and cytokines in neuropathic pain. This investigation was designed to evaluate the interaction between co-administration of ceftriaxone, a specific GLT1 activator and minocycline, a specific microglia inhibitor, on the mechanical and cold allodynia of chronic constriction injury model (CCI) in rats. Moreover, alteration of the spinal concentration of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was studied. Ceftriaxone (100, 150 and 200mg/kg, i.p.) and minocycline (25, 50 and 100mg/kg, i.p.) were administered either alone or in combination for 7 days. Gabapentin (100mg/kg, i.p.) was selected as a reference drug. Behavioral evaluations were performed 1 day before and on days 3, 5, 7, 10 and 14 after surgery. Each of drugs produced a dose-dependent reversal of the neuropathic pain behaviors. Area under the curve (AUC) of combination therapy revealed that minocycline potentiated cold and mechanical antiallodynic effects of ceftriaxone. TNF-α and IL-1β increased in the spinal cord of CCI animals on days 3, 7 and 14 post-surgery. Production of studied cytokines was significantly attenuated after treatment with ceftriaxone alone and in combination with minocycline compared with control group. It is suggested that combination of these classes of drugs would be a promising approach for treatment of chronic neuropathic pain.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Ceftriaxone; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hyperalgesia; Male; Minocycline; Neuralgia; Rats; Rats, Wistar; Sciatic Neuropathy; Spinal Cord