4-aminopyrrolidine-2-4-dicarboxylic-acid and Pain

This study sought to evaluate whether peripheral group II and III metabotropic glutamate receptors (mGluRs) in the knee joint have inhibitory effects on carrageenan-induced nociceptive behavior. To this end, changes in weight load and hind paw withdrawal threshold were measured in rats following the administration of specific peripheral group II and III mGluR agonists 30min before (induction phase) and 4h after (maintenance phase) the injection of carrageenan (1%, 50μl). During the induction phase of arthritic pain, a significant recovery of reduced weight load occurred after the administration of 500μM APDC ((2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate; group II agonist) and 100 and 500μM L-AP4 (l-2-amino-4-phosphonobutylate; group III agonist). Similarly, 100 and 500μM APDC and 500μM L-AP4 significantly reduced mechanical hyperalgesia during the induction phase. In the maintenance phase, APDC at all doses (10, 100 and 500μM) and 100 and 500μM L-AP4 significantly counteracted the reduction in weight load, and APDC and L-AP4 at all doses (10, 100 and 500μM) inhibited mechanical hyperalgesia. The current study suggests that peripheral group II and III mGluRs in the knee joint negatively modulates nociceptive behavior during both the induction and maintenance phases of carrageenan-induced arthritic pain.

Topics: Animals; Arthritis, Experimental; Behavior, Animal; Carrageenan; Hindlimb; Hyperalgesia; Joints; Male; Nociception; Pain; Pain Threshold; Physical Stimulation; Proline; Propionates; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Weight-Bearing

Despite the importance of spinal metabotropic glutamate receptors (mGluRs) and opioid receptors in nociceptive processing, the roles of these receptors in the modulation of neuropathic pain at the spinal level have not been thoroughly investigated. The purpose of this study was to investigate the effects of spinal mGluR agents and opioids (morphine) on neuropathic pain. Male Sprague-Dawley rats underwent L5 and L6 spinal nerve ligation to induce neuropathic pain and intrathecal catheterization for drug administration. A paw-withdrawal threshold to mechanical stimulus was measured using the "up and down" method. When administered intrathecally, neither Group I mGluR antagonists nor Group II or III agonists modified the withdrawal threshold after spinal nerve ligation. Intrathecal administration of morphine dose-dependently increased the withdrawal threshold. Whereas ACPT-III, a Group III mGluR agonist, enhanced the antiallodynic action of morphine, other mGluR agents did not. Collectively, mGluRs may not directly modulate the processing of spinal nerve ligation-induced neuropathic pain at the spinal level. However, Group III mGluR agonists in the spinal cord may indirectly contribute to the potentiation of morphine antiallodynia, indicating that these agonists might be used as adjuvants for spinal morphine.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Synergism; Excitatory Amino Acid Agonists; Ligation; Male; Morphine; Neuralgia; Pain; Pain Measurement; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Nerves; Treatment Outcome

Transient receptor potential vanilloid 1 (TRPV1) receptors are critical to nociceptive processing. Understanding how these receptors are modulated gives insight to potential therapies for pain. We demonstrate using double labeling immunohistochemistry that Group II metabotropic glutamate receptors (mGluRs) are co-expressed with TRPV1 on rat dorsal root ganglion (DRG) cells. In behavioral studies, intraplantar 0.1 microM APDC, a group II agonist, significantly attenuates capsaicin-induced nociceptive behaviors through a local effect. The APDC-induced inhibition of capsaicin responses is blocked by 1 microM LY341495, a group II antagonist. At the single fiber level, nociceptor responses to capsaicin are significantly decreased following exposure to APDC and this effect is blocked by LY341495. Finally, activation of peripheral group II mGluRs inhibits forskolin-induced thermal hyperalgesia and nociceptor heat sensitization, suggesting group II receptors are negatively coupled to the cAMP/PKA pathway. The data indicate that group II mGluRs and TRPV1 receptors are co-expressed on peripheral nociceptors and activation of mGluRs can inhibit painful sensory transmission following TRPV1 activation. The data are consistent with group II and TRPV1 receptors being linked intracellularly by the cAMP/PKA pathway. Peripheral group II mGluRs are important targets for drug discovery in controlling TRPV1-induced nociception.

Topics: Amino Acids; Animals; Capsaicin; Colforsin; Electrophysiological Phenomena; Ganglia, Spinal; Hot Temperature; Hyperalgesia; Immunohistochemistry; Male; Nociceptors; Pain; Pain Measurement; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; TRPV Cation Channels; Xanthenes

Metabotropic glutamate receptor (mGluR) 2/3 is distributed in neurons and glial cells in many regions of the nervous system, but its role in nociceptive processing is unclear. In this study, we examined the mRNA expressions of mGluR2 and mGluR3, by real-time RT-PCR, in the spinal cord. We further investigated the possible involvement of mGluR2/3 and mechanisms underlying peripheral inflammatory pain induced by subcutaneous complete Freund's adjuvant (CFA) injection. We demonstrate that compared to the controls, the mRNA expression levels of mGluR2 and mGluR3 were significantly higher 4h after CFA injection. Functionally, blocking mGluR2/3 by their antagonist (2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) alleviated the CFA-induced mechanical allodynia and the inhibitory effects were reversed by mGluR2/3 agonist (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R, 4R)-APDC). In addition, a glial metabolism inhibitor dl-fluorocitric acid barium salt (fluorocitric acid) also inhibited the CFA-induced mechanical allodynia in a dose-dependent manner. Remarkably, simultaneous inhibition of mGluR2/3 and glial metabolism had synergistic effects. The co-administration of LY341495 and fluorocitric acid with minimal dosages produced significant more inhibition than the additive effects by the individual inhibitor alone. In summary, our data suggest that spinal mGluR2/3 contributes to the generation of mechanical allodynia induced by peripheral inflammation. We also suggest that involvement of mGluR2/3 in the communication between glial cells and neurons takes part in the processing of nociceptive information.

Topics: Amino Acids; Analgesics; Animals; Citrates; Dose-Response Relationship, Drug; Freund's Adjuvant; Hyperesthesia; Inflammation; Male; Neuroglia; Pain; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Spinal Cord; Xanthenes

The present study investigated the involvement of spinal glutamate receptors in the induction and maintenance of the pain-related behaviors induced by the venom of scorpion Buthus martensi Karsch (BmK). (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-10-imine hydrogen maleate (MK-801; 40nmol; a non-competitive NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 40nmol; a non-NMDA receptor antagonist), dl-amino-3-phosphonopropionic acid (dl-AP3; 100nmol; a group I metabotropic glutamate receptor antagonist) and 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 100nmol; a group II metabotropic glutamate receptor agonist) were employed. On intrathecal injection of glutamate receptor antagonists/agonist before BmK venom administration by 10min, BmK venom-induced spontaneous nociceptive responses could be suppressed by all tested agents. Primary thermal hyperalgesia could be inhibited by MK-801 and dl-AP3, while bilateral mechanical hyperalgesia could be inhibited by CNQX and dl-AP3 and contralateral mechanical hyperalgesia could be inhibited by APDC. On intrathecal injection of glutamate receptor antagonists/agonist after BmK venom injection by 4.5h, primary thermal hyperalgesia could be partially reversed by all tested agents, while bilateral mechanical hyperalgesia could only be inhibited by APDC. The results suggest that the role of spinal glutamate receptors may be different on the various manifestations of BmK venom-induced pain-related behaviors.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Alanine; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Pain; Proline; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Scorpion Venoms