6-cyano-7-nitroquinoxaline-2-3-dione and Peripheral-Nervous-System-Diseases

In the brain, transmembrane AMPAR regulatory proteins (TARPs) critically influence the distribution, gating, and pharmacology of AMPARs, but the contribution of these auxiliary subunits to AMPAR-mediated signaling in the spinal cord remains unclear. We found that the Type I TARP γ-2 (stargazin) is present in lamina II of the superficial dorsal horn, an area involved in nociception. Consistent with the notion that γ-2 is associated with surface AMPARs, CNQX, a partial agonist at AMPARs associated with Type I TARPs, evoked whole-cell currents in lamina II neurons, but such currents were severely attenuated in γ-2-lacking

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Calcium Channels; Capsaicin; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Female; Inflammation; Male; Mice; Mice, Inbred C57BL; Nerve Fibers, Unmyelinated; Neuronal Plasticity; Peripheral Nervous System Diseases; Posterior Horn Cells; Receptors, AMPA; Synaptic Transmission

Temporal properties of spike firing in the central nervous system (CNS) are critical for neuronal coding and the precision of information storage. Chronic pain has been reported to affect cognitive and emotional functions, in addition to trigger long-term plasticity in sensory synapses and behavioral sensitization. Less is known about the possible changes in temporal precision of cortical neurons in chronic pain conditions. In the present study, we investigated the temporal precision of action potential firing in the anterior cingulate cortex (ACC) by using both in vivo and in vitro electrophysiological approaches. We found that peripheral inflammation caused by complete Freund's adjuvant (CFA) increased the standard deviation (SD) of spikes latency (also called jitter) of ∼51% of recorded neurons in the ACC of adult rats in vivo. Similar increases in jitter were found in ACC neurons using in vitro brain slices from adult mice with peripheral inflammation or nerve injury. Bath application of glutamate receptor antagonists CNQX and AP5 abolished the enhancement of jitter induced by CFA injection or nerve injury, suggesting that the increased jitter depends on the glutamatergic synaptic transmission. Activation of adenylyl cyclases (ACs) by bath application of forskolin increased jitter, whereas genetic deletion of AC1 abolished the change of jitter caused by CFA inflammation. Our study provides strong evidence for long-term changes of temporal precision of information coding in cortical neurons after peripheral injuries and explains neuronal mechanism for chronic pain caused cognitive and emotional impairment.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Cognition; Disease Models, Animal; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Gyrus Cinguli; In Vitro Techniques; Mice; Mice, Inbred C57BL; Neurons; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Valine

Large-conductance calcium-activated potassium channels (BK channels) have been suggested to play a substantial role in synaptic transmission in the spinal cord dorsal horn. In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of synaptic transmission in the superficial dorsal horn where nociceptive information is processed. Spontaneously occurring excitatory postsynaptic currents (sEPSCs) were recorded from the neurons located in the superficial dorsal horn of a mouse spinal cord slice, and the effects of iberiotoxin, a BK channel blocker, on sEPSCs were analyzed. The frequency of sEPSCs was significantly higher in the peripheral nerve-ligated neuropathic mice than in the sham-operated control mice, but the amplitude of sEPSCs was equivalent between the two groups. Iberiotoxin increased the frequency of sEPSCs in the control mice to the same level as that in the neuropathic mice without affecting the amplitude of sEPSCs. In contrast, iberiotoxin did not show any significant effects on the sEPSCs in the neuropathic mice. These findings suggest that the BK channels that are located in presynaptic terminals control synaptic transmission in the superficial dorsal horn, and that functional downregulation of BK channels accompanies the neuropathic pain induced by peripheral nerve injury. This downregulation was confirmed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of the BK channel alpha subunit. Taken together, our present results indicate that BK channels play crucial roles in the synaptic transmission of nociceptive information in the superficial dorsal horn.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Down-Regulation; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; In Vitro Techniques; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Mice; Mice, Inbred ICR; Patch-Clamp Techniques; Peptides; Peripheral Nervous System Diseases; Posterior Horn Cells; Presynaptic Terminals; Spinal Cord; Synaptic Transmission

We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. Capsaicin cream applied to both the bilateral hind instep and sole once a day for a continuous period of 2 weeks or 4 weeks alleviated thermal hyperalgesia in a dose-dependent manner. A remarkable effect was observed 2 weeks after the start of the application and this effect proved to be reversible. On the other hand, in sham-operated animals when capsaicin cream was applied once daily from day 7 after the sham operation, from 1 day through 3 weeks following capsaicin application, withdrawal latency of the sham-operated paws of the capsaicin-treated group was significantly increased as compared to that of the vehicle cream-treated group. The effects of antagonists of glutamate receptor and tachykinin receptors were investigated 7 days post surgery. Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Animals; Benzamides; Capsaicin; Carrageenan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Indoles; Isoindoles; Male; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Piperidines; Postoperative Period; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Substance Withdrawal Syndrome; Time Factors

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Pain; Peripheral Nervous System Diseases; Pyrrolidinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sciatic Nerve