Role In Central Sensitization Research Articles

Glutamate Receptor Antagonists

GLUR5 Antagonists as Novel Migraine TherapiesBACKGROUND: L‐glutamate activates neurons in the trigeminal nucleus caudalis (TNC). Furthermore, non‐NMDA ionotropic glutamate receptors such as GluR5 are expressed in rat trigeminal ganglion (TG), and GluR5 receptors play an important role in central sensitization (CS). CS is implicated in, and the trigeminal system is at the core of, migraine. Therefore, we hypothesized that GluR5 receptor antagonists would be effective in preclinical models of migraine.OBJECTIVES: 1) To test the potency and efficacy of GluR5 antagonists with varying degrees of affinity and selectivity for the GluR5/kainate receptor in the dural plasma protein extravasation (PPE) and the c‐fos models of migraine. 2) To test these GluR5 receptor antagonists for their ability to contract the rabbit saphenous vein (RSV) in vitro.METHODS: GluR5 antagonists were synthesized in the Lilly Research Laboratories. Ligand binding studies using recombinant human non‐NMDA receptors expressed in HEK293 cell membranes were used to determine compound affinity. We evaluated parenterally administered compounds in the PPE and the c‐fos models induced by electrical stimulation of male rats TG. Fos protein in the TNC was measured in the c‐fos experiment. Ring preparations of RSV were suspended in tissue baths and isometric contractions were recorded following incremental increases in the concentration of the test compound. Sumatriptan was used as a positive control for the RSV studies.RESULTS: LY293558, LY382884 and LY435735 dose‐dependently blocked protein extravasation in the PPE model. The rank order of potency correlated with affinity for GluR5. In contrast, LY300168, a potent and selective AMPA antagonist, did not block protein extravasation, even at relatively high doses. LY293558 and LY435735 also blocked c‐fos expression in the TNC. LY293558 and LY382884 did not contract the tissue in the RSV assay at concentrations up to 100 mM.CONCLUSIONS: The inhibitory effects of GluR5 antagonists in the PPE and c‐fos preclinical models of migraine suggest a novel role for GluR5 antagonism in migraine therapy. The lack of efficacy of the selective AMPA antagonist LY300168 in PPE does not support a role for this mechanism in migraine. The lack of activity of these compounds in the RSV provides a therapeutic advantage of GluR5 antagonists over current vasoactive migraine therapies. These pharmacological properties of GluR5 antagonists suggest that they could be used in the treatment of acute migraine without a cardiovascular liability.

Role of COX-2 Inhibitors in the Evolution of Acute Pain Management

Management of acute postoperative pain remains suboptimal: nearly 80% of patients report moderate to extreme pain following surgery. New pain management paradigms incorporate multimodal analgesia, using a combination of analgesics throughout the perioperative period to control nociceptive and centrally-stimulated pain. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) have a role in postoperative pain management, but concerns about increased bleeding and inhibited wound healing and bone fusion have limited their use. Cyclooxygenase (COX)-2-selective inhibitors (coxibs) offer the peripheral pain-relieving benefits of nonselective NSAIDs but with fewer adverse GI effects; they also may have a role in central sensitization. Clinical trials have demonstrated the efficacy and safety of celecoxib and rofecoxib for postoperative pain and for preemptive analgesia, and newer agents such as valdecoxib and etoricoxib also have demonstrated efficacy in these settings. In addition to their selectivity for the COX-2 isozyme overall, unique differences among the coxibs, such as in plasma half-life, may impart certain clinical advantages.

The role of nitric oxide in the phosphorylation of cyclic adenosine monophosphate—responsive element-binding protein in the spinal cord after intradermal injection of capsaicin

We investigated the involvement of nitric oxide (NO) in the phosphorylation of cyclic adenosine monophosphate-responsive element-binding protein (CREB) in the spinal cord of rats during central sensitization after intradermal capsaicin injection. CREB and phosphorylated CREB (p-CREB) were measured by immunoblotting. The level of p-CREB increased by 20 minutes, peaked between 20 and 60 minutes after capsaicin injection, and started to decrease after 150 minutes. CREB itself did not show an obvious change after capsaicin injection. The p-CREB expression on the ipsilateral side of the spinal dorsal horn, but not on the contralateral side, increased significantly after capsaicin injection. The increase in p-CREB induced by capsaicin injection was partially blocked by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, administered through a microdialysis fiber placed across the spinal cord. D-NAME, an inactive form of L-NAME, had no effect. CREB phosphorylation, not the level of CREB, was induced within 20 minutes by microdialysis administration of SIN-1, an NO donor. These results indicate that CREB phosphorylation in the spinal cord results from both endogenous and exogenous NO release and that p-CREB may play a role in central sensitization or in longer-term changes in gene expression induced by strong peripheral noxious stimulation. © 2002 by the American Pain Society

The Effect of an Intravenous Ketamine Infusion on a Patient Who Had Suffered from Postherpetic Neuralgia

people recover from herpes zoster with no pain, but some patients, especially elderly people, go to the state of postherpetic neuralgia. Herpes zoster viruses destroy all the nerves from skin to dorsal root ganglion and nerves at the spinal level. After this central sensitization, abnormal ephaptic relays occur. Patients complain of allodynia, spontaneous burning pain, paroxysmal lancinating pain, and dullness on the lesion site. Now many remedies are available but a panacea does not exist. Ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) receptor that has a crucial role in central sensitization. We met a 66-year-old woman who had suffered from postherpetic neuralgia for 10 years. We tried nerve blocks several times and medicated with various drugs but the outcome was not satisfactory. Lastly we tried ketamine infusion therapy and the result was excellent.

Spinal NK1 receptor is upregulated after chronic bladder irritation

It has been suggested that there is a significant upregulation of the NK1 receptor (NK1R) on neurons in the dorsal spinal cord after long-term somatic inflammation. This upregulation appears to play a significant role in central sensitization in chronic pain states. However, it is not clear whether such a change is also observed after chronic visceral (bladder) inflammation. Changes in NK1R immunoreactivity after chronic bladder irritation were investigated in order to evaluate the existence of hypersensitive states in the spinal cord after chronic bladder irritation. Experiments were performed on a total of 12 adult female Sprague–Dawley rats. In six animals, cyclophosphamide (CPA) was administered intraperitoneally for 2 weeks. Another six animals were given intraperitoneal saline injections and served as the control group. After these treatments, immunohistochemical staining for NK1Rs and substance P in rat lumbosacral spinal cord was performed. In CPA-treated animals, NK1R-positive areas and staining intensity within the dorsal spinal cord were significantly increased in the L5 to S2 spinal cord areas, especially in the L6 and S1 segments. In the L6 spinal segment, CPA-treatment enhanced NK1R immunostaining in the medial and the lateral dorsal horn, as well as in the lateral laminae including the sacral parasympathetic nucleus to a lesser extent. In CPA-treated animals, substance P staining intensity increased in the same regions in which NK1R immunoreactivity was increased. This finding probably implies the upregulation of spinal NK1R and the occurrence of central sensitization within the spinal cord after chronic visceral inflammation.

Duodenal acid infusion causes esophageal hypersensitivity: Role of central sensitization in functional gut disorders

Duodenal acid infusion causes esophageal hypersensitivity: Role of central sensitization in functional gut disorders

Topical ketamine gel: possible role in treating neuropathic pain.

Neuropathic pain is often resistant to opioids, so other medication classes, such as tricyclic antidepressants, anticonvulsants, and local anesthetics, are often used. Central sensitization, or pain 'wind-up', may perpetuate chronic neuropathic pain even when ongoing peripheral sensory input is absent. Wind-up is thought to cause allodynia, hyperalgesia, and hyperpathia. Receptors such as NMDA, AMPA, and M-glu have recently been identified for their role in central sensitization or pain 'wind-up'. Ketamine has been proposed recently for neuropathic pain secondary to its NMDA receptor activity. The current application as a topical gel stems from the theory that ketamine has peripheral action at both opioid and Na+-K+ channels. This case study involved 5 patients from 25 to 70 years old (3 RSD, 1 lumbar radiculopathy, 1 post-herpetic neuralgia). Dose used was determined by site and surface area of involvement and ranged from 0.093 mg/kg to 9.33 mg/kg. All five patients reported significant pain relief at initial application and wished to continue treatment. The average numerical analogue scale (NAS) score preapplication was 8.8. The average 15 minutes post application NAS was 1.6. Patients reported alterations in temperature sensation, feelings of relaxation and decreased tension in the area of application, and pain relief. Reduction in numerical pain scores postapplication of ketamine gel ranged from 53-100% using a 1-10 numerical pain intensity scale. No significant side effects were reported. Ketamine Gel may provide clinicians with a new option in the battle against chronic neuropathic pain. Until further information is available and larger trials can be conducted, we can only recommend this type of therapy for refractory cases in which all primary and secondary options have been exhausted.

Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.

Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.