Objectives: The conformational state of voltage-gated sodium channels is an important determinant... more Objectives: The conformational state of voltage-gated sodium channels is an important determinant for the efficacy of both local anesthesia and electrical neuromodulation techniques. This study investigated the role of subthreshold preconditioning ramp currents on axonal nerve excitability parameters in the presence of sodium channel blockers in myelinated A and unmyelinated C fibers. Materials and Methods: A-and C-fiber compound action potentials were recorded extracellularly in vitro in saphenous nerve from adult rats. Nerve fibers were stimulated with a supramaximal current pulse either alone or after a 300-msec conditioning polarizing ramp current (between-10% and +100% of the original threshold current) in the presence and absence of lidocaine and tetrodotoxin (TTX). A computerized threshold tracking program (QTRAC
Contrasting findings have been published regarding the role of magnesium sulphate used as an addi... more Contrasting findings have been published regarding the role of magnesium sulphate used as an additive to local anaesthetics in peripheral nerve blocks. To clarify the effect of magnesium sulphate on nerve excitability. C and Aβ compound action potentials were recorded extracellularly in vitro in saphenous nerves from adult rats. Saphenous nerves (n = 30) from male Wistar rats (n = 19), 12 to 16 weeks old. Primary sensory afferents were tested with a computerised threshold tracking program (QTRAC) with a supramaximal 1 ms current pulse either alone or after 300 ms of conditioning polarising ramp currents in the presence and absence of 10 mmol l magnesium sulphate, 80 μmol l lidocaine and a combination of both. Changes in current thresholds to elicit compound action potential amplitudes of 40% of the maximal response. Magnesium sulphate increased excitability thresholds to a greater extent in Aβ fibres than in C fibres. It enhanced the effects of lidocaine in both Aβ fibres [mixture 0.470 mA (SD 0.105) versus lidocaine 0.358 mA (SD 0.080), P < 0.001] and C fibres [mixture 2.531 mA (SD 0.752) versus lidocaine 2.385 mA (SD 0.656), P = 0.008]. Preconditioning experiments also showed that magnesium sulphate had an enhancing effect with lidocaine in Aβ fibres [mixture 0.620 mA (SD 0.281) versus lidocaine 0.543 mA (SD 0.315), P = 0.005], but not in C fibres [mixture 2.412 mA (SD 0.641), lidocaine 2.461 mA (SD 0.693), P = 0.17]. These results suggest that the binding of magnesium ions depends on both the type and conformational state of voltage-gated sodium channels. They also may help to explain the conflicting reports regarding the clinical effects of magnesium sulphate as an additive to lidocaine in peripheral nerve blocks.
Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli... more Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli in primate hairy skin, have not been described in glabrous skin. The aim of this study was to assess the effect of hairy and glabrous skin stimulation on neural transmission of nociceptive inputs elicited by different kinds of thermal heating. We recorded and analysed automatically at a single-trial level the brain potentials evoked by heat stimuli (thermal radiation, LEPs, and thermal conduction, CHEPs) of hand dorsum and palm in healthy volunteers. Laser stimulation of hairy and glabrous skin at the same energy elicited remarkably similar psychophysical ratings and LEPs. This finding provides evidence that first pain to heat does exist in glabrous skin, and suggests that similar type-II like nociceptive afferents mediate first pain to heat stimulation of glabrous and hairy skin in humans. In contrast, CHEPs following glabrous skin stimulation had significantly longer latencies (N2-wave: +25%, P2-wave: +24%) and smaller amplitudes (N2-wave: −40%, P2-wave: −44%). Independently of the stimulated territory, CHEPs always had significantly longer latencies (hairy skin: N2-wave: +75%, P2-wave: +56%) and smaller amplitudes (hairy skin N2-wave: −42%, P2-wave: −19%) than LEPs. These findings are consistent with the thickness-dependent delay and attenuation of the temperature waveform at nociceptor level when conductive heating is applied, and suggest that the previously reported lack of first pain and microneurographical type II AMH responses following glabrous skin stimulation could have been the result of a search bias consequent to the use of long-wavelength radiant heating as stimulation procedure.
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Background: Streptozotocin produces diabetes and diabetic neuropathy in experimental animals. Res... more Background: Streptozotocin produces diabetes and diabetic neuropathy in experimental animals. Results: Streptozotocin stimulates TRPA1 through oxidation of cysteine residues, which leads to acute sensory changes in vivo. Conclusion: Cysteine oxidation is a novel mechanism of action for streptozotocin. Significance: The diabetogenic agent streptozotocin induces acute sensory changes prior to the onset of diabetes.
bioRxiv (Cold Spring Harbor Laboratory), Sep 3, 2022
TRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhib... more TRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhibition or genetic ablation of TRPA1 profoundly reduces normal behavioural sensitivity to noxious cold and mechanical stimulation, as well as sensory neuron responses to mechanical stimulation. TRPA1 inhibition also reverses cold and mechanical hypersensitivities in chronic pain models in vivo. Here we demonstrate that these striking effects of TRPA1 inactivation result from an increased constitutive activity of kappa opioid receptors (KOR) co-expressed with TRPA1 in sensory neurons. Inhibition of KOR in Trpa1-/mice restores nociception and neuronal activity to the levels observed in wild-type mice and reverses the analgesic effects of TRPA1 antagonism in naïve mice and in neuropathic and inflammatory pain conditions. TRPA1 regulation of KOR activity in sensory neurons provides a novel mechanism to produce peripherally mediated analgesia. Our findings suggest that TRP channel regulation of constitutive GPCR activity, may be a process of general physiological importance.
† Intraoperative neuromonitoring can be affected by specific general anaesthetics. † Changes in a... more † Intraoperative neuromonitoring can be affected by specific general anaesthetics. † Changes in axonal excitability of primary sensory afferents with propofol and sevoflurane were investigated using threshold tracking technique. † Both anaesthetics similarly affected nerve excitability to a small but significant extent. † Possible mechanisms include direct anaesthetic effects on neuronal excitability and temperature change due to vasodilation. Background. Intraoperative monitoring of neuronal function is important in a variety of surgeries. The type of general anaesthetic used can affect the interpretation and quality of such recordings. Although the principal effects of general anaesthetics are synaptically mediated, the extent to which they affect excitability of the peripheral afferent nervous system is unclear. Methods. Forty subjects were randomized in a stratified manner into two groups, anaesthetized with either propofol or sevoflurane. The threshold tracking technique (QTRAC w) was used to measure nerve excitability parameters of the sensory action potential of the median nerve before and after induction of general anaesthesia. Results. Several parameters of peripheral sensory afferent nerve excitability changed after induction of general anaesthesia, which were similar for both propofol and sevoflurane. The maximum amplitude of the sensory nerve action potential decreased in both groups (propofol: 25.3%; sevoflurane: 29.5%; both P,0.01). The relative refractory period [mean (SD)] also decreased similarly in both groups [propofol: 20.6 (0.7) ms; sevoflurane: 20.3 (0.5) ms; both P,0.01]. Skin temperature at the stimulation site increased significantly in both groups [propofol: +1.2 (1.0)8C; sevoflurane: +1.7 (1.4)8C; both P,0.01]. Conclusions. Small changes in excitability of primary sensory afferents after the induction of anaesthesia with propofol or sevoflurane were detected. These effects, which were nonspecific and are possibly explained by changes observed in temperature, demonstrate possible anaesthetic effects on intraoperative neuromonitoring.
ABSTRACTTRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacologic... more ABSTRACTTRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhibition or genetic ablation of TRPA1 profoundly reduces normal behavioural sensitivity to noxious cold and mechanical stimulation, as well as sensory neuron responses to mechanical stimulation. TRPA1 inhibition also reverses cold and mechanical hypersensitivities in chronic pain models in vivo. Here we demonstrate that these striking effects of TRPA1 inactivation result from an increased constitutive activity of kappa opioid receptors (KOR) co-expressed with TRPA1 in sensory neurons. Inhibition of KOR in Trpa1-/- mice restores nociception and neuronal activity to the levels observed in wild-type mice and reverses the analgesic effects of TRPA1 antagonism in naïve mice and in neuropathic and inflammatory pain conditions. TRPA1 regulation of KOR activity in sensory neurons provides a novel mechanism to produce peripherally mediated analgesia. Our findings suggest that TRP channel reg...
The role of temperature sensations elicited from the skin, include object identification, thermor... more The role of temperature sensations elicited from the skin, include object identification, thermoregulation and the conscious perception of pain. Humans can differentiate at least three distinct cold sensations: innocuous cooling, cold pain and pain evoked by freezing. However, patients with painful neuropathies often suffer from cold allodynia, where normally non-painful cool stimuli begin to induce pain or cold hyperalgesia, a heightened sensitivity to a painful cold stimulus. It is therefore vital to understand the mechanisms by which cold is signalled under normal conditions and to investigate which changes occur under pathological conditions. The thesis will describe sets of electrophysiological recordings carried out from rodent primary afferent neurons using the in vitro skin nerve preparation in an attempt to reveal mechanisms underlying thermal sensitivity. The discovery of thermally sensitive transient receptor potential (TRP) ion channels has given insights into the molecu...
SUMMARYFibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain a... more SUMMARYFibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain and tenderness1,2. The etiology and pathophysiology of fibromyalgia are unknown and there are no effective treatments. Here we show that sensory hypersensitivity in FMS is caused by autoantibodies that act by sensitizing nociceptive sensory neurons. Administration of IgG from FMS patients increased mouse pain sensitivities to stimulation with mechanical pressure and cold. In contrast, transfer of IgG depleted samples from FMS patients or IgG from healthy control subjects had no effect on pain sensitivity. Sensory nerve fibres in ex vivo skin-nerve preparations from mice treated with FMS IgG were hypersensitive to mechanical stimulation. Immunohistochemical analysis revealed that IgG from FMS patients specifically labeled satellite glial cells and myelinated fibre tracts, as well as a small number of macrophages and endothelial cells in mouse dorsal root ganglia but not skin, muscle, spina...
The mechanisms responsible for painful and insensate diabetic neuropathy are not completely under... more The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplanta...
Background: Nerve growth factor (NGF) elevates expression of ion channels and receptors contribut... more Background: Nerve growth factor (NGF) elevates expression of ion channels and receptors contributing to pain. This study investigates the role of NGF in the up-regulation of the number and efficacy of sensory neuron m-opioid receptors (MOR) rendering sites of painful inflammation more susceptible to opioids. Methods: Following intraplantar Freunds Complete Adjuvant (FCA) or NGF treatment, MOR expression in DRG, MOR axonal transport, MORimmunoreactive (ir) subcutaneous nerve endings as well as its impact on peripheral fentanyl-induced antinociception were assessed in rats. Finally, prevention of all these effects by NGF neutralization was examined. Results: MOR colocalized with CGRP and with TrkA and p75 NTR receptors within rat DRG. FCA or NGF treatment increased MOR expression in DRG, MOR axonal transport and subsequently MOR-ir subcutaneous nerve fibers. Furthermore, peripheral antinociception elicited by intraplantar fentanyl was potentiated exclusively in inflamed and NGF treated paws. Both FCAand NGF-induced effects were abrogated by NGF neutralization. Conclusions: Our results suggest that NGF not only contributes to inflammatory pain but also to an upregulation in the number and efficacy of sensory neuron MOR, resulting in an enhanced opioid susceptibility towards better pain control. This implies the potential to overcome the unresponsiveness to opioids of certain neuropathic pain states.
Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli... more Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli in primate hairy skin, have not been described in glabrous skin. The aim of this study was to assess the effect of hairy and glabrous skin stimulation on neural transmission of nociceptive inputs elicited by different kinds of thermal heating. We recorded and analysed automatically at a single-trial level the brain potentials evoked by heat stimuli (thermal radiation, LEPs, and thermal conduction, CHEPs) of hand dorsum and palm in healthy volunteers. Laser stimulation of hairy and glabrous skin at the same energy elicited remarkably similar psychophysical ratings and LEPs. This finding provides evidence that first pain to heat does exist in glabrous skin, and suggests that similar type-II like nociceptive afferents mediate first pain to heat stimulation of glabrous and hairy skin in humans. In contrast, CHEPs following glabrous skin stimulation had significantly longer latencies (N2-wave: +25%, P2-wave: +24%) and smaller amplitudes (N2-wave: −40%, P2-wave: −44%). Independently of the stimulated territory, CHEPs always had significantly longer latencies (hairy skin: N2-wave: +75%, P2-wave: +56%) and smaller amplitudes (hairy skin N2-wave: −42%, P2-wave: −19%) than LEPs. These findings are consistent with the thickness-dependent delay and attenuation of the temperature waveform at nociceptor level when conductive heating is applied, and suggest that the previously reported lack of first pain and microneurographical type II AMH responses following glabrous skin stimulation could have been the result of a search bias consequent to the use of long-wavelength radiant heating as stimulation procedure.
Objectives: The conformational state of voltage-gated sodium channels is an important determinant... more Objectives: The conformational state of voltage-gated sodium channels is an important determinant for the efficacy of both local anesthesia and electrical neuromodulation techniques. This study investigated the role of subthreshold preconditioning ramp currents on axonal nerve excitability parameters in the presence of sodium channel blockers in myelinated A and unmyelinated C fibers. Materials and Methods: A-and C-fiber compound action potentials were recorded extracellularly in vitro in saphenous nerve from adult rats. Nerve fibers were stimulated with a supramaximal current pulse either alone or after a 300-msec conditioning polarizing ramp current (between-10% and +100% of the original threshold current) in the presence and absence of lidocaine and tetrodotoxin (TTX). A computerized threshold tracking program (QTRAC
Contrasting findings have been published regarding the role of magnesium sulphate used as an addi... more Contrasting findings have been published regarding the role of magnesium sulphate used as an additive to local anaesthetics in peripheral nerve blocks. To clarify the effect of magnesium sulphate on nerve excitability. C and Aβ compound action potentials were recorded extracellularly in vitro in saphenous nerves from adult rats. Saphenous nerves (n = 30) from male Wistar rats (n = 19), 12 to 16 weeks old. Primary sensory afferents were tested with a computerised threshold tracking program (QTRAC) with a supramaximal 1 ms current pulse either alone or after 300 ms of conditioning polarising ramp currents in the presence and absence of 10 mmol l magnesium sulphate, 80 μmol l lidocaine and a combination of both. Changes in current thresholds to elicit compound action potential amplitudes of 40% of the maximal response. Magnesium sulphate increased excitability thresholds to a greater extent in Aβ fibres than in C fibres. It enhanced the effects of lidocaine in both Aβ fibres [mixture 0.470 mA (SD 0.105) versus lidocaine 0.358 mA (SD 0.080), P < 0.001] and C fibres [mixture 2.531 mA (SD 0.752) versus lidocaine 2.385 mA (SD 0.656), P = 0.008]. Preconditioning experiments also showed that magnesium sulphate had an enhancing effect with lidocaine in Aβ fibres [mixture 0.620 mA (SD 0.281) versus lidocaine 0.543 mA (SD 0.315), P = 0.005], but not in C fibres [mixture 2.412 mA (SD 0.641), lidocaine 2.461 mA (SD 0.693), P = 0.17]. These results suggest that the binding of magnesium ions depends on both the type and conformational state of voltage-gated sodium channels. They also may help to explain the conflicting reports regarding the clinical effects of magnesium sulphate as an additive to lidocaine in peripheral nerve blocks.
Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli... more Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli in primate hairy skin, have not been described in glabrous skin. The aim of this study was to assess the effect of hairy and glabrous skin stimulation on neural transmission of nociceptive inputs elicited by different kinds of thermal heating. We recorded and analysed automatically at a single-trial level the brain potentials evoked by heat stimuli (thermal radiation, LEPs, and thermal conduction, CHEPs) of hand dorsum and palm in healthy volunteers. Laser stimulation of hairy and glabrous skin at the same energy elicited remarkably similar psychophysical ratings and LEPs. This finding provides evidence that first pain to heat does exist in glabrous skin, and suggests that similar type-II like nociceptive afferents mediate first pain to heat stimulation of glabrous and hairy skin in humans. In contrast, CHEPs following glabrous skin stimulation had significantly longer latencies (N2-wave: +25%, P2-wave: +24%) and smaller amplitudes (N2-wave: −40%, P2-wave: −44%). Independently of the stimulated territory, CHEPs always had significantly longer latencies (hairy skin: N2-wave: +75%, P2-wave: +56%) and smaller amplitudes (hairy skin N2-wave: −42%, P2-wave: −19%) than LEPs. These findings are consistent with the thickness-dependent delay and attenuation of the temperature waveform at nociceptor level when conductive heating is applied, and suggest that the previously reported lack of first pain and microneurographical type II AMH responses following glabrous skin stimulation could have been the result of a search bias consequent to the use of long-wavelength radiant heating as stimulation procedure.
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
Background: Streptozotocin produces diabetes and diabetic neuropathy in experimental animals. Res... more Background: Streptozotocin produces diabetes and diabetic neuropathy in experimental animals. Results: Streptozotocin stimulates TRPA1 through oxidation of cysteine residues, which leads to acute sensory changes in vivo. Conclusion: Cysteine oxidation is a novel mechanism of action for streptozotocin. Significance: The diabetogenic agent streptozotocin induces acute sensory changes prior to the onset of diabetes.
bioRxiv (Cold Spring Harbor Laboratory), Sep 3, 2022
TRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhib... more TRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhibition or genetic ablation of TRPA1 profoundly reduces normal behavioural sensitivity to noxious cold and mechanical stimulation, as well as sensory neuron responses to mechanical stimulation. TRPA1 inhibition also reverses cold and mechanical hypersensitivities in chronic pain models in vivo. Here we demonstrate that these striking effects of TRPA1 inactivation result from an increased constitutive activity of kappa opioid receptors (KOR) co-expressed with TRPA1 in sensory neurons. Inhibition of KOR in Trpa1-/mice restores nociception and neuronal activity to the levels observed in wild-type mice and reverses the analgesic effects of TRPA1 antagonism in naïve mice and in neuropathic and inflammatory pain conditions. TRPA1 regulation of KOR activity in sensory neurons provides a novel mechanism to produce peripherally mediated analgesia. Our findings suggest that TRP channel regulation of constitutive GPCR activity, may be a process of general physiological importance.
† Intraoperative neuromonitoring can be affected by specific general anaesthetics. † Changes in a... more † Intraoperative neuromonitoring can be affected by specific general anaesthetics. † Changes in axonal excitability of primary sensory afferents with propofol and sevoflurane were investigated using threshold tracking technique. † Both anaesthetics similarly affected nerve excitability to a small but significant extent. † Possible mechanisms include direct anaesthetic effects on neuronal excitability and temperature change due to vasodilation. Background. Intraoperative monitoring of neuronal function is important in a variety of surgeries. The type of general anaesthetic used can affect the interpretation and quality of such recordings. Although the principal effects of general anaesthetics are synaptically mediated, the extent to which they affect excitability of the peripheral afferent nervous system is unclear. Methods. Forty subjects were randomized in a stratified manner into two groups, anaesthetized with either propofol or sevoflurane. The threshold tracking technique (QTRAC w) was used to measure nerve excitability parameters of the sensory action potential of the median nerve before and after induction of general anaesthesia. Results. Several parameters of peripheral sensory afferent nerve excitability changed after induction of general anaesthesia, which were similar for both propofol and sevoflurane. The maximum amplitude of the sensory nerve action potential decreased in both groups (propofol: 25.3%; sevoflurane: 29.5%; both P,0.01). The relative refractory period [mean (SD)] also decreased similarly in both groups [propofol: 20.6 (0.7) ms; sevoflurane: 20.3 (0.5) ms; both P,0.01]. Skin temperature at the stimulation site increased significantly in both groups [propofol: +1.2 (1.0)8C; sevoflurane: +1.7 (1.4)8C; both P,0.01]. Conclusions. Small changes in excitability of primary sensory afferents after the induction of anaesthesia with propofol or sevoflurane were detected. These effects, which were nonspecific and are possibly explained by changes observed in temperature, demonstrate possible anaesthetic effects on intraoperative neuromonitoring.
ABSTRACTTRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacologic... more ABSTRACTTRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhibition or genetic ablation of TRPA1 profoundly reduces normal behavioural sensitivity to noxious cold and mechanical stimulation, as well as sensory neuron responses to mechanical stimulation. TRPA1 inhibition also reverses cold and mechanical hypersensitivities in chronic pain models in vivo. Here we demonstrate that these striking effects of TRPA1 inactivation result from an increased constitutive activity of kappa opioid receptors (KOR) co-expressed with TRPA1 in sensory neurons. Inhibition of KOR in Trpa1-/- mice restores nociception and neuronal activity to the levels observed in wild-type mice and reverses the analgesic effects of TRPA1 antagonism in naïve mice and in neuropathic and inflammatory pain conditions. TRPA1 regulation of KOR activity in sensory neurons provides a novel mechanism to produce peripherally mediated analgesia. Our findings suggest that TRP channel reg...
The role of temperature sensations elicited from the skin, include object identification, thermor... more The role of temperature sensations elicited from the skin, include object identification, thermoregulation and the conscious perception of pain. Humans can differentiate at least three distinct cold sensations: innocuous cooling, cold pain and pain evoked by freezing. However, patients with painful neuropathies often suffer from cold allodynia, where normally non-painful cool stimuli begin to induce pain or cold hyperalgesia, a heightened sensitivity to a painful cold stimulus. It is therefore vital to understand the mechanisms by which cold is signalled under normal conditions and to investigate which changes occur under pathological conditions. The thesis will describe sets of electrophysiological recordings carried out from rodent primary afferent neurons using the in vitro skin nerve preparation in an attempt to reveal mechanisms underlying thermal sensitivity. The discovery of thermally sensitive transient receptor potential (TRP) ion channels has given insights into the molecu...
SUMMARYFibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain a... more SUMMARYFibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain and tenderness1,2. The etiology and pathophysiology of fibromyalgia are unknown and there are no effective treatments. Here we show that sensory hypersensitivity in FMS is caused by autoantibodies that act by sensitizing nociceptive sensory neurons. Administration of IgG from FMS patients increased mouse pain sensitivities to stimulation with mechanical pressure and cold. In contrast, transfer of IgG depleted samples from FMS patients or IgG from healthy control subjects had no effect on pain sensitivity. Sensory nerve fibres in ex vivo skin-nerve preparations from mice treated with FMS IgG were hypersensitive to mechanical stimulation. Immunohistochemical analysis revealed that IgG from FMS patients specifically labeled satellite glial cells and myelinated fibre tracts, as well as a small number of macrophages and endothelial cells in mouse dorsal root ganglia but not skin, muscle, spina...
The mechanisms responsible for painful and insensate diabetic neuropathy are not completely under... more The mechanisms responsible for painful and insensate diabetic neuropathy are not completely understood. Here, we have investigated sensory neuropathy in the mouse, a hereditary model of diabetes. Akita mice become diabetic soon after weaning, and we show that this is accompanied by an impaired mechanical and thermal nociception and a significant loss of intraepidermal nerve fibers. Electrophysiological investigations of skin-nerve preparations identified a reduced rate of action potential discharge in mechanonociceptors compared with wild-type littermates, whereas the function of low-threshold A-fibers was essentially intact. Studies of isolated sensory neurons demonstrated a markedly reduced heat responsiveness in dorsal root ganglion (DRG) neurons, but a mostly unchanged function of cold-sensitive neurons. Restoration of normal glucose control by islet transplantation produced a rapid recovery of nociception, which occurred before normoglycemia had been achieved. Islet transplanta...
Background: Nerve growth factor (NGF) elevates expression of ion channels and receptors contribut... more Background: Nerve growth factor (NGF) elevates expression of ion channels and receptors contributing to pain. This study investigates the role of NGF in the up-regulation of the number and efficacy of sensory neuron m-opioid receptors (MOR) rendering sites of painful inflammation more susceptible to opioids. Methods: Following intraplantar Freunds Complete Adjuvant (FCA) or NGF treatment, MOR expression in DRG, MOR axonal transport, MORimmunoreactive (ir) subcutaneous nerve endings as well as its impact on peripheral fentanyl-induced antinociception were assessed in rats. Finally, prevention of all these effects by NGF neutralization was examined. Results: MOR colocalized with CGRP and with TrkA and p75 NTR receptors within rat DRG. FCA or NGF treatment increased MOR expression in DRG, MOR axonal transport and subsequently MOR-ir subcutaneous nerve fibers. Furthermore, peripheral antinociception elicited by intraplantar fentanyl was potentiated exclusively in inflamed and NGF treated paws. Both FCAand NGF-induced effects were abrogated by NGF neutralization. Conclusions: Our results suggest that NGF not only contributes to inflammatory pain but also to an upregulation in the number and efficacy of sensory neuron MOR, resulting in an enhanced opioid susceptibility towards better pain control. This implies the potential to overcome the unresponsiveness to opioids of certain neuropathic pain states.
Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli... more Type II A-fibre nociceptors (AMHs), the peripheral afferents mediating first pain to heat stimuli in primate hairy skin, have not been described in glabrous skin. The aim of this study was to assess the effect of hairy and glabrous skin stimulation on neural transmission of nociceptive inputs elicited by different kinds of thermal heating. We recorded and analysed automatically at a single-trial level the brain potentials evoked by heat stimuli (thermal radiation, LEPs, and thermal conduction, CHEPs) of hand dorsum and palm in healthy volunteers. Laser stimulation of hairy and glabrous skin at the same energy elicited remarkably similar psychophysical ratings and LEPs. This finding provides evidence that first pain to heat does exist in glabrous skin, and suggests that similar type-II like nociceptive afferents mediate first pain to heat stimulation of glabrous and hairy skin in humans. In contrast, CHEPs following glabrous skin stimulation had significantly longer latencies (N2-wave: +25%, P2-wave: +24%) and smaller amplitudes (N2-wave: −40%, P2-wave: −44%). Independently of the stimulated territory, CHEPs always had significantly longer latencies (hairy skin: N2-wave: +75%, P2-wave: +56%) and smaller amplitudes (hairy skin N2-wave: −42%, P2-wave: −19%) than LEPs. These findings are consistent with the thickness-dependent delay and attenuation of the temperature waveform at nociceptor level when conductive heating is applied, and suggest that the previously reported lack of first pain and microneurographical type II AMH responses following glabrous skin stimulation could have been the result of a search bias consequent to the use of long-wavelength radiant heating as stimulation procedure.
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