ABSTRACT
Title
Metabotropic glutamate receptors as targets for drugs of potential use in chronic pain conditions
Authors
S. Chiechio
Department of Drug Sciences, University of Catania
Department of Drug Sciences, University of Catania
Abstract
Chronic pain reflects the development of mechanisms leading to an increased transmission within the entire pain neuraxis. This phenomenon, known as nociceptive sensitization, explains most of the clinical signs of chronic pain such as hyperalgesia, allodynia, and spontaneous pain [1].
Metabotropic glutamate receptors (mGlu) are key players pain sensitization. These receptors form a family of eight subtypes (mGlu1-8) divided into three groups on the basis of their aminoacid sequence, pharmacological profile and transduction pathways. Group I includes mGlu1 and mGlu5 receptors, which are coupled to Gq/G11 proteins, whereas group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7 and mGlu8) receptor subtypes are coupled to Gi/Go proteins [2].
All mGlu receptor subtypes (with the exception of mGlu6 receptors) are widely distributed in all brain regions involved in pain, in the spinal cord and in dorsal root ganglia, and are implicated in the induction, expression, and maintenance of nociceptive sensitization [3-6]
Pharmacological blockade of group I mGlu receptors is analgesic in models of inflammatory and neuropathic pain. On the contrary, activation of group II and III mGlu receptors inhibits hyperalgesia in models of inflammatory and neuropathic pain [5,6] pain transmission at the synapses between primary afferent fibers and second order neurons in the dorsal horn of the spinal cord. In addition, mGlu2/3 receptors are found in peripheral nociceptors, and in pain-regulatory centers of the brainstem and forebrain.
It is here proposed a new therapeutic strategy based on the transcriptional regulation of mGlu2 receptors via the acetylation of the p65/RelA transcription factor. A selective up-regulation of mGlu2 receptors in the spinal cord and in dorsal root ganglia was induced by repeated injection of two histone deacetylases (HDAC) inhibitors, SAHA (5-50 mg/kg, sc) and MS275 (3 mg/kg, sc), or by the acetylating drug L-acetylcarnitine (100 mg/kg, sc). Chronic treatment with these drugs also induced an increased acetylation of the p65/RelA transcription factor of the NF-kB family. Interestingly these drugs induced analgesia in models of inflammatory and neuropathic pain and the analgesic effect was reversed by a single injection of the mGlu2/3 receptor antagonist LY341495 (1 mg/kg, ip).
The predominant role of mGlu2 receptors in the control of pain transmission was demonstrated by using mGlu2 and mGlu3 knock-out mice in a model of inflammatory pain, the formalin test. mGlu2 knock-out mice displayed a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2 knock-out mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3 knock-out mice did not significantly differ from their wild type littermates in either phase of the formalin test. When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3 knock-out but not in mGlu2 knock-out mice.
Taken together, these results demonstrate that mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice and suggest that an increased expression of mGlu2 receptors could reduce the expression of nociceptive sensitization by reinforcing one of the major endogenous mechanisms that negatively regulates the release of glutamate, substance P, and other pain transmitters.
[1] Basbaum, A. I. et al. (2009) .Cell 139, 267–284.
[2] Pin, J. P. and Duvoisin, R. (1995). Trends Pharmacol. Sci. 22, 114–120
[3]Neugebauer, V. et al. (2000). J. Neurophysiol. 84,2998–3009.
[4] Varney, M. A. and Gereau, R. W., IV (2002). Curr. Drug Targets CNS Neurol. Disord. 1, 283–296.
[5]Goudet, C. et al. (2008).Pain 137, 112–124.
[6] Jones, C. K. et al. (2005). Neuropharmacology 49, 206–218.
Metabotropic glutamate receptors (mGlu) are key players pain sensitization. These receptors form a family of eight subtypes (mGlu1-8) divided into three groups on the basis of their aminoacid sequence, pharmacological profile and transduction pathways. Group I includes mGlu1 and mGlu5 receptors, which are coupled to Gq/G11 proteins, whereas group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7 and mGlu8) receptor subtypes are coupled to Gi/Go proteins [2].
All mGlu receptor subtypes (with the exception of mGlu6 receptors) are widely distributed in all brain regions involved in pain, in the spinal cord and in dorsal root ganglia, and are implicated in the induction, expression, and maintenance of nociceptive sensitization [3-6]
Pharmacological blockade of group I mGlu receptors is analgesic in models of inflammatory and neuropathic pain. On the contrary, activation of group II and III mGlu receptors inhibits hyperalgesia in models of inflammatory and neuropathic pain [5,6] pain transmission at the synapses between primary afferent fibers and second order neurons in the dorsal horn of the spinal cord. In addition, mGlu2/3 receptors are found in peripheral nociceptors, and in pain-regulatory centers of the brainstem and forebrain.
It is here proposed a new therapeutic strategy based on the transcriptional regulation of mGlu2 receptors via the acetylation of the p65/RelA transcription factor. A selective up-regulation of mGlu2 receptors in the spinal cord and in dorsal root ganglia was induced by repeated injection of two histone deacetylases (HDAC) inhibitors, SAHA (5-50 mg/kg, sc) and MS275 (3 mg/kg, sc), or by the acetylating drug L-acetylcarnitine (100 mg/kg, sc). Chronic treatment with these drugs also induced an increased acetylation of the p65/RelA transcription factor of the NF-kB family. Interestingly these drugs induced analgesia in models of inflammatory and neuropathic pain and the analgesic effect was reversed by a single injection of the mGlu2/3 receptor antagonist LY341495 (1 mg/kg, ip).
The predominant role of mGlu2 receptors in the control of pain transmission was demonstrated by using mGlu2 and mGlu3 knock-out mice in a model of inflammatory pain, the formalin test. mGlu2 knock-out mice displayed a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2 knock-out mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3 knock-out mice did not significantly differ from their wild type littermates in either phase of the formalin test. When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3 knock-out but not in mGlu2 knock-out mice.
Taken together, these results demonstrate that mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice and suggest that an increased expression of mGlu2 receptors could reduce the expression of nociceptive sensitization by reinforcing one of the major endogenous mechanisms that negatively regulates the release of glutamate, substance P, and other pain transmitters.
[1] Basbaum, A. I. et al. (2009) .Cell 139, 267–284.
[2] Pin, J. P. and Duvoisin, R. (1995). Trends Pharmacol. Sci. 22, 114–120
[3]Neugebauer, V. et al. (2000). J. Neurophysiol. 84,2998–3009.
[4] Varney, M. A. and Gereau, R. W., IV (2002). Curr. Drug Targets CNS Neurol. Disord. 1, 283–296.
[5]Goudet, C. et al. (2008).Pain 137, 112–124.
[6] Jones, C. K. et al. (2005). Neuropharmacology 49, 206–218.