... Terence J. Coderre Corresponding Author Contact Information , Robert W. Grimes and RonaldMelz... more ... Terence J. Coderre Corresponding Author Contact Information , Robert W. Grimes and RonaldMelzack. Department of Psychology, McGill University, 1205 Docteur Penfield Ave., Montreal, Que. H3A 1B1, Canada. Received 11 December 1985; accepted 6 February 1986. ...
We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the fo... more We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persis- tent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
The contribution of intracellular calcium to central sensitization and persistent nociception in ... more The contribution of intracellular calcium to central sensitization and persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin injury-induced nociceptive behaviors were enhanced by intrathecal pretreatment with the calcium ionophore A23187 or the calcium channel agonist Bay-K8644. Conversely, formalin nociceptive responses were reduced by intrathecal pretreatment with the calcium chelator Quin 2 or the calcium channel antagonists verapamil and nifedipine. Each of these agents affected the tonic, but not the acute, phase of the formalin response. The enhancement in formalin nociceptive behavior in rats treated with L-aspartate or L-glutamate was reversed by combined pretreatment with the noncompetitive NMDA antagonist MK-801, but not by nifedipine or the non-NMDA excitatory amino acid antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione. In rats not treated with excitatory amino acids, the analg...
Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by ... more Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Behavioral, electrophysiological, and autoradiographic experiments were done to study the second ... more Behavioral, electrophysiological, and autoradiographic experiments were done to study the second nociceptive phase in the formalin test. In initial experiments, this second phase was attenuated by 1-10 mg of the NK-1 receptor antagonist CP-99,994, given subcutaneously 10, 30, or 60 min before formalin (n = 8-10) and by 20 microgram given intrathecally 20 min after formalin (n = 13); the inactive isomer CP-100,263 was ineffective. In electrophysiological experiments on single dorsal horn neurons in vivo, the excitatory responses to subcutaneous formalin injection (50 microliter, 2.5%) were attenuated by subsequent intravenously administration of the NK-1 receptor antagonist CP-96,345 (0.5 mg/kg; n = 8), given 35-40 min after formalin, but not by the inactive enantiomer CP-96,344 (0.5 mg/kg; n = 9). Finally, autoradiographic binding of exogenous [(125)I]BH-substance P in the lumbar cord was reduced at 5 and 25 min after formalin (50 microliter, 1 or 5%), with an intermediate level of ...
The Journal of pharmacology and experimental therapeutics, 1995
Experiments were performed to investigate the possible involvement of spinal mu-, delta- and kapp... more Experiments were performed to investigate the possible involvement of spinal mu-, delta- and kappa-opiate receptors in mediating the antinociceptive effects of noxious thermal stimulation of one hindpaw on the tail flick reflex in the rat. Male Sprague-Dawley rats were implanted with chronic intrathecal catheters to the lumbar level of the spinal cord. After 5 to 7 days, they were lightly anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail flick test a conditioning noxious thermal stimulus, which consisted of immersion of one hindpaw in water at 55 degrees C for 90 sec, was applied and the effects on the latency of the tail withdrawal reflex were studied over the next 30 min. In animals pretreated with CSF intrathecally 10 min before the stimulus, an increase in tail flick reaction time was observed peaking at 30 sec after the stimulus. This response was attenuated in a dose-r...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1995
We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the fo... more We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persistent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal stimulation. Furthermore, we have assessed changes in membrane-associated PKC in spinal cord in response to both noxious chemical and thermal stimulation. Nociceptive responses, to a hindpaw injection of 50 microliters of 2.5% formalin, and flexion reflex thresholds, to mechanical stimulation (Randall-Selitto test) in the hindpaw contralateral to a thermal injury (15 sec immersion in water at 55 degrees C), were assessed following intrathecal injection of PKC inhibitors (GF 109203X or chelerythrine). Changes in the levels of membrane-associated PKC, as assayed by quantitative autorad...
The effects of peripheral adrenergic depleting agents on the threshold for non-damaging heat pain... more The effects of peripheral adrenergic depleting agents on the threshold for non-damaging heat pain (tail-flick test), inflammatory pain associated with tissue injury (formalin test), and chronic pain or dysaesthesia associated with nerve lesions (autotomy test) were examined. Tail-flick latencies were increased by agents which deplete peripheral adrenergic transmitters--6-hydroxydopamine (6-OHDA) and guanethidine--as well as by an agent which prevents the synthesis of noradrenaline--FLA63. A combination of guanethidine and FLA63 also increased latencies, but no more than either treatment alone. Formalin pain scores were reduced by FLA63+ guanethidine and 6-OHDA, but not by guanethidine or FLA63 alone. The percentage of rats that exhibited autotomy was reduced minimally by 6-OHDA and guanethidine treatments which started the day of surgery, maximally by guanethidine treatments which started 4 days before surgery, and not at all by guanethidine treatments which started 4 days after sur...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1992
The contribution of excitatory amino acids (EAAs) to the development of central sensitization and... more The contribution of excitatory amino acids (EAAs) to the development of central sensitization and persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin-induced nociceptive behaviors were enhanced by intrathecal pretreatment with the EAAs L-glutamate and L-aspartate. An enhancement of the formalin nociceptive response was also produced by intrathecal pretreatment with the receptor-selective EAA agonists NMDA and trans-(+/- )-1-amino-1,3-cyclopentane dicarboxylic acid (ACPD), but not (R,S)-alpha-amino-3-hydroxy-5-methylisozazole-4-propionic acid hydrobromide (AMPA). The effect of NMDA was enhanced by a combined administration with AMPA or APCD. Formalin nociceptive responses were dose-dependently reduced by intrathecal pretreatment with the NMDA receptor antagonists 2-amino-5-phosphonovaleric acid (APV) and (+)-MK-801 hydrogen maleate, but not the selective AMPA antagonist 6-cyano-7-nitroqui...
ABSTRACT Although opioids are the most commonly used analgesics, their therapeutic efficacy is li... more ABSTRACT Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca2+). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.
High-resolution (500 MHz) multiresonance/multinuclear proton (1H) nuclear magnetic resonance (NMR... more High-resolution (500 MHz) multiresonance/multinuclear proton (1H) nuclear magnetic resonance (NMR) spectroscopy was used to detect metabolic changes and cellular injury in the rat brain stem and spinal cord following chronic morphine treatment. Compensatory changes were observed in glycine, glutamate, and inositols in the brain stem, but not the spinal cord, of chronic morphine-treated rats. In spinal cord, increases were detected in lactate and N-acetyl-aspartate (NAA), suggesting that there is anaerobic glycolysis, plasma membrane damage, and altered pH preferentially in the spinal cord of chronic morphine-treated rats.
The formalin test is a well-established model for assessing inflammatory nociceptive processes an... more The formalin test is a well-established model for assessing inflammatory nociceptive processes and analgesic drug effects. Previous research established the validity of an ordinal relationship among three well-defined pain behavior categories used to compute a composite pain score (CPS). However, optimal weights had not been validated. The present research used data from Coderre et al. (1993) and from Sufka and Roach (1996) to determine and validate optimal pain behavior category weights. Based on multiple regression analyses and Pearson correlations, optimal weights of 1 and 2 are proposed for behavior categories 2 and 3, respectively; behavior category 1 is not scored. These results are consistent with the work of Abbott et al. (1995) and Coderre et al. (1993) in that the ordinal relationship among category weights is preserved, and extend previous work by establishing optimal category weights.
In the present study, we examined the effects of intrathecal pretreatment (twice daily injections... more In the present study, we examined the effects of intrathecal pretreatment (twice daily injections on postoperative (PO) days 0-3 with the selective Group I (mGluR1a) mGluR antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid ((RS)-AIDA), the selective Group I (mGluR5a) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the selective Group II mGluR agonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC) or the selective Group III mGluR agonist, L-2-amino-4-phosphonobutyrate (L-AP4), on mechanical and cold hypersensitivity associated with chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical and cold sensitivity was assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. Pretreatment with all of the mGluR agents produced reductions in the development of mechanical hypersensitivity. In addition, all the mGluR agents, except MPEP, were effective in reducing the development of cold hypersensitivity. This study demonstrates that spinal Group I mGluR antagonism, and Group II or III mGluR agonism, can effectively decrease the development of mechanical and cold hypersensitivity associated with CCI in rats. In addition, the results can be interpreted to suggest that activation of spinal Group I mGluRs contributes to spinal plasticity leading to the development of neuropathic pain, and that this effect is offset by activation of groups II and III mGluRs.
... Terence J. Coderre Corresponding Author Contact Information , Robert W. Grimes and RonaldMelz... more ... Terence J. Coderre Corresponding Author Contact Information , Robert W. Grimes and RonaldMelzack. Department of Psychology, McGill University, 1205 Docteur Penfield Ave., Montreal, Que. H3A 1B1, Canada. Received 11 December 1985; accepted 6 February 1986. ...
We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the fo... more We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persis- tent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
The contribution of intracellular calcium to central sensitization and persistent nociception in ... more The contribution of intracellular calcium to central sensitization and persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin injury-induced nociceptive behaviors were enhanced by intrathecal pretreatment with the calcium ionophore A23187 or the calcium channel agonist Bay-K8644. Conversely, formalin nociceptive responses were reduced by intrathecal pretreatment with the calcium chelator Quin 2 or the calcium channel antagonists verapamil and nifedipine. Each of these agents affected the tonic, but not the acute, phase of the formalin response. The enhancement in formalin nociceptive behavior in rats treated with L-aspartate or L-glutamate was reversed by combined pretreatment with the noncompetitive NMDA antagonist MK-801, but not by nifedipine or the non-NMDA excitatory amino acid antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione. In rats not treated with excitatory amino acids, the analg...
Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by ... more Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
Behavioral, electrophysiological, and autoradiographic experiments were done to study the second ... more Behavioral, electrophysiological, and autoradiographic experiments were done to study the second nociceptive phase in the formalin test. In initial experiments, this second phase was attenuated by 1-10 mg of the NK-1 receptor antagonist CP-99,994, given subcutaneously 10, 30, or 60 min before formalin (n = 8-10) and by 20 microgram given intrathecally 20 min after formalin (n = 13); the inactive isomer CP-100,263 was ineffective. In electrophysiological experiments on single dorsal horn neurons in vivo, the excitatory responses to subcutaneous formalin injection (50 microliter, 2.5%) were attenuated by subsequent intravenously administration of the NK-1 receptor antagonist CP-96,345 (0.5 mg/kg; n = 8), given 35-40 min after formalin, but not by the inactive enantiomer CP-96,344 (0.5 mg/kg; n = 9). Finally, autoradiographic binding of exogenous [(125)I]BH-substance P in the lumbar cord was reduced at 5 and 25 min after formalin (50 microliter, 1 or 5%), with an intermediate level of ...
The Journal of pharmacology and experimental therapeutics, 1995
Experiments were performed to investigate the possible involvement of spinal mu-, delta- and kapp... more Experiments were performed to investigate the possible involvement of spinal mu-, delta- and kappa-opiate receptors in mediating the antinociceptive effects of noxious thermal stimulation of one hindpaw on the tail flick reflex in the rat. Male Sprague-Dawley rats were implanted with chronic intrathecal catheters to the lumbar level of the spinal cord. After 5 to 7 days, they were lightly anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail flick test a conditioning noxious thermal stimulus, which consisted of immersion of one hindpaw in water at 55 degrees C for 90 sec, was applied and the effects on the latency of the tail withdrawal reflex were studied over the next 30 min. In animals pretreated with CSF intrathecally 10 min before the stimulus, an increase in tail flick reaction time was observed peaking at 30 sec after the stimulus. This response was attenuated in a dose-r...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1995
We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the fo... more We have previously suggested that protein kinase C (PKC) contributes to persistent pain in the formalin test. This study compared the effects of pharmacological inhibition of PKC with either GF 109203X or chelerythrine on persistent pain following noxious chemical stimulation with its effects on mechanical hyperalgesia, which develops in the hindpaw contralateral to an injury produced by noxious thermal stimulation. Furthermore, we have assessed changes in membrane-associated PKC in spinal cord in response to both noxious chemical and thermal stimulation. Nociceptive responses, to a hindpaw injection of 50 microliters of 2.5% formalin, and flexion reflex thresholds, to mechanical stimulation (Randall-Selitto test) in the hindpaw contralateral to a thermal injury (15 sec immersion in water at 55 degrees C), were assessed following intrathecal injection of PKC inhibitors (GF 109203X or chelerythrine). Changes in the levels of membrane-associated PKC, as assayed by quantitative autorad...
The effects of peripheral adrenergic depleting agents on the threshold for non-damaging heat pain... more The effects of peripheral adrenergic depleting agents on the threshold for non-damaging heat pain (tail-flick test), inflammatory pain associated with tissue injury (formalin test), and chronic pain or dysaesthesia associated with nerve lesions (autotomy test) were examined. Tail-flick latencies were increased by agents which deplete peripheral adrenergic transmitters--6-hydroxydopamine (6-OHDA) and guanethidine--as well as by an agent which prevents the synthesis of noradrenaline--FLA63. A combination of guanethidine and FLA63 also increased latencies, but no more than either treatment alone. Formalin pain scores were reduced by FLA63+ guanethidine and 6-OHDA, but not by guanethidine or FLA63 alone. The percentage of rats that exhibited autotomy was reduced minimally by 6-OHDA and guanethidine treatments which started the day of surgery, maximally by guanethidine treatments which started 4 days before surgery, and not at all by guanethidine treatments which started 4 days after sur...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1992
The contribution of excitatory amino acids (EAAs) to the development of central sensitization and... more The contribution of excitatory amino acids (EAAs) to the development of central sensitization and persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin-induced nociceptive behaviors were enhanced by intrathecal pretreatment with the EAAs L-glutamate and L-aspartate. An enhancement of the formalin nociceptive response was also produced by intrathecal pretreatment with the receptor-selective EAA agonists NMDA and trans-(+/- )-1-amino-1,3-cyclopentane dicarboxylic acid (ACPD), but not (R,S)-alpha-amino-3-hydroxy-5-methylisozazole-4-propionic acid hydrobromide (AMPA). The effect of NMDA was enhanced by a combined administration with AMPA or APCD. Formalin nociceptive responses were dose-dependently reduced by intrathecal pretreatment with the NMDA receptor antagonists 2-amino-5-phosphonovaleric acid (APV) and (+)-MK-801 hydrogen maleate, but not the selective AMPA antagonist 6-cyano-7-nitroqui...
ABSTRACT Although opioids are the most commonly used analgesics, their therapeutic efficacy is li... more ABSTRACT Although opioids are the most commonly used analgesics, their therapeutic efficacy is limited by the development of tolerance and dependence with chronic use. Many studies have examined the possible mechanisms underlying the development of opioid tolerance and dependence. Recently, several groups of investigators have focused on excitatory amino acid receptors, specifically N-methyl-D-aspartate (NMDA) receptors, and related intracellular second messenger systems as possible mediators of opioid tolerance and dependence. The hypothesis proposed in this Focus article is an extension of these models of opioid tolerance and dependence, which suggests that metabotropic glutamate receptors (mGluRs) play a key role in the development of opioid tolerance and dependence. We propose that activity at group I mGluRs (and possibly also δ-opioid receptors), which are positively coupled to phosphatidylinositol (PI) hydrolysis, increases during chronic morphine administration. This ultimately leads to increased activation of protein kinase C, with concomitant phosphorylation of μ-opioid receptors (desensitizing them), and the ion channel associated with the NMDA receptor (allowing increased influx of Ca2+). We also suggest that there is a heterologous desensitization of group II and III mGluRs, which are negatively coupled to cyclic adenosine monophosphate (cAMP) production, contributing to the increased cAMP production seen during opioid dependence and withdrawal. Thus, although we agree with previous investigators about the importance of NMDA receptors, we hypothesize that mGluRs also play a critical role in the contribution of excitatory amino acids to opioid tolerance and dependence.
High-resolution (500 MHz) multiresonance/multinuclear proton (1H) nuclear magnetic resonance (NMR... more High-resolution (500 MHz) multiresonance/multinuclear proton (1H) nuclear magnetic resonance (NMR) spectroscopy was used to detect metabolic changes and cellular injury in the rat brain stem and spinal cord following chronic morphine treatment. Compensatory changes were observed in glycine, glutamate, and inositols in the brain stem, but not the spinal cord, of chronic morphine-treated rats. In spinal cord, increases were detected in lactate and N-acetyl-aspartate (NAA), suggesting that there is anaerobic glycolysis, plasma membrane damage, and altered pH preferentially in the spinal cord of chronic morphine-treated rats.
The formalin test is a well-established model for assessing inflammatory nociceptive processes an... more The formalin test is a well-established model for assessing inflammatory nociceptive processes and analgesic drug effects. Previous research established the validity of an ordinal relationship among three well-defined pain behavior categories used to compute a composite pain score (CPS). However, optimal weights had not been validated. The present research used data from Coderre et al. (1993) and from Sufka and Roach (1996) to determine and validate optimal pain behavior category weights. Based on multiple regression analyses and Pearson correlations, optimal weights of 1 and 2 are proposed for behavior categories 2 and 3, respectively; behavior category 1 is not scored. These results are consistent with the work of Abbott et al. (1995) and Coderre et al. (1993) in that the ordinal relationship among category weights is preserved, and extend previous work by establishing optimal category weights.
In the present study, we examined the effects of intrathecal pretreatment (twice daily injections... more In the present study, we examined the effects of intrathecal pretreatment (twice daily injections on postoperative (PO) days 0-3 with the selective Group I (mGluR1a) mGluR antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid ((RS)-AIDA), the selective Group I (mGluR5a) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the selective Group II mGluR agonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC) or the selective Group III mGluR agonist, L-2-amino-4-phosphonobutyrate (L-AP4), on mechanical and cold hypersensitivity associated with chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical and cold sensitivity was assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. Pretreatment with all of the mGluR agents produced reductions in the development of mechanical hypersensitivity. In addition, all the mGluR agents, except MPEP, were effective in reducing the development of cold hypersensitivity. This study demonstrates that spinal Group I mGluR antagonism, and Group II or III mGluR agonism, can effectively decrease the development of mechanical and cold hypersensitivity associated with CCI in rats. In addition, the results can be interpreted to suggest that activation of spinal Group I mGluRs contributes to spinal plasticity leading to the development of neuropathic pain, and that this effect is offset by activation of groups II and III mGluRs.
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