Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones

doi:10.1016/0006-8993(95)01063-7

Brain Research

Volume 703, Issues 1–2, 12 December 1995, Pages 45-50

https://doi.org/10.1016/0006-8993(95)01063-7 Get rights and content

Abstract

The responses of convergent dorsal horn neurones to peripheral injection of formalin (5% formaldehyde, 50 μl volume) were recorded extracellularly in the halothane anaesthetized rat. The control response of dorsal horn neurones to formalin was biphasic, with a first phase from 0–10 min and the second inflammatory phase from 10–60 min. Pre-administered intrathecal CNQX (5, 50 and 500 μg), 5 min before formalin injection, significantly reduced both the first phase (40 ± 22, 52 ± 20 and 40 ± 28% inhibition, respectively,P < 0.05)and the second phase of the formalin response (40 ± 20% inhibition,P < 0.05, 93 ± 4% inhibition,P < 0.0001 and 65 ± 17% inhibition,P < 0.05, respectively). Post-administered CNQX, administered 5 min after the peripheral injection of formalin, was less efficacious, as compared to pre-administered CNQX, at reducing the second phase of the formalin response. The lowest dose of post-administered CNQX (5 μg) facilitated the second phase of the response (47 ± 19% facilitation,P < 0.05), and the higher dose (50 μg) produced smaller inhibitions of the response (42 ± 10% inhibition,P < 0.05 than those observed with pre-administration of the same dose. However, the highest dose of CNQX (500 μg) studied produced similar inhibitions of the second phase of the formalin response, irrespective of the timing of administration. Intrathecal administration of 7-chlorokynurenate (7CK, 0.25-2.5 μg), a functional antagonist at the glycine site of the NMDA receptor, did not alter the first phase of the formalin response. The second phase of the formalin response was significantly inhibited, and to a similar extent, by both pre- and post-administration of 2.5 μg of 7CK (67 ± 10% and 56 ± 7% inhibition respectively,P < 0.05 for both). Overall, our results clearly demonstrate differential time-related roles of different transmitter systems in the induction and maintenance of inflammatory evoked persistent pain responses, and such events may become increasingly relevant to the control of pain in the clinic.

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All efforts were made to decrease bias and to increase reproducibility (Andrews et al., 2016) as described in the method details below. Intraplanar injection of formalin initiates increases in spontaneous activity of c-fibers and discharge of wide dynamic range neurons, observed initially in spinal cord neurons (Chapman and Dickenson, 1995). Behaviorally, this neuronal excitability manifests as biphasic bouts of nocifensive responding.
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Our results have shown, for the first time, that administration of CXCL17 in naïve mice induced strong pain-related behaviours, as measured by von Frey and cold plate tests. Moreover, we demonstrated that kynurenic acid and zaprinast diminished CXCL17-evoked pain-related behaviours in both tests. Kynurenic acid and zaprinast reduced thermal and tactile hypersensitivity developed by sciatic nerve injury and strongly enhanced the effectiveness of morphine in neuropathy.
Our study highlights the importance of GPR35 as a receptor involved in neuropathic pain development. Therefore, these results suggest that the modulation of GPR35 could become a potential strategy for the treatment of neuropathic pain.
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These studies show that systemic administration of the prodrug 4-Cl-KYN produces high central nervous system levels of 7-Cl-KYNA, a potent and highly selective antagonist of the NMDA receptor. Compared with other drugs tested, 4-Cl-KYN has robust antinociceptive effects with a better side effect profile, highlighting its potential for treating hyperpathic pain states.
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Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.
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It is evident that RNAi-mediated knockdown of NR1 does not completely block phase 2 formalin response, a finding similar to that observed with antisense39 and conditional knockout.42 Whereas the magnitude of knockdown may somewhat parallel the reduction in phase 2 response, it is more likely that other systems such as the non-NMDA glutamatergic receptors6 and pronociceptive neuropeptides5,23 make significant contributions to this nociceptive response. In contrast to the phase 2 formalin response, mechanical allodynia occurring at 24 hours after intraplantar formalin is completely blocked in vector 6 animals, suggesting that the maintenance of mechanical allodynia is entirely NMDA-receptor dependent, and, as previously reported, centrally mediated.41,45,47
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It is widely accepted that NMDA receptors also play an important role in nociceptive processing, but most of them prove to be effective on nociception only in doses with adverse effects. This may be caused by the widespread nature of the glutamate excitatory transmitter system and its involvement in many important physiological processes (Chapman and Dickenson, 1995; Yaksh, 1989; Yamamoto et al., 1993; Coderre and Empel, 1994; Joo et al., 2000; Ren et al., 1992). The proposed endogenous ligand of the NMDA receptor, KYNA, has been poorly investigated in terms of its analgesic properties at spinal level (Kekesi et al., 2002; Näsström et al., 1992; Yamamoto and Yaksh, 1992).
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Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones

Abstract

Pain

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Neuropharmacology

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