The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans... more The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finall...
Intraoperative lung-protective ventilation (ILPV) is defined as tidal volumes <8 mL/kg ide... more Intraoperative lung-protective ventilation (ILPV) is defined as tidal volumes <8 mL/kg ideal bodyweight and is increasingly a standard of care for major abdominal surgical procedures performed under general anesthesia. In this study, we report the result of a quality improvement initiative targeted at improving adherence to ILPV guidelines in a large academic teaching hospital. We performed a time-series study to determine whether anesthesia provider adherence to ILPV was affected by certain improvement interventions and patient ideal body weight (IBW). Tidal volume data were collected at 3 different time points for 191 abdominal surgical cases from June 2014 through April 2015. Improvement interventions during that period included education at departmental grand rounds, creation of a departmental ILPV policy, feedback of tidal volume and failure rate data at grand rounds sessions, and reducing default ventilator settings for tidal volume. Mean tidal volume per kilogram of ideal body weight (VT/kg IBW) and rates of noncompliance with ILPV were analyzed before and after the interventions. A survey was administered to assess provider attitudes after implementation of improvement interventions. Responses before and after interventions and between physician and nonphysician providers were analyzed. Reductions in mean VT/kg IBW and rates of failure for providers to use ILPV occurred after improvement interventions. Patients with IBW <65 kg received higher VT/kg IBW and had higher rates of failure to use ILPV than patients with IBW >65 kg. Surveyed providers demonstrated stronger agreement to having knowledge and practice consistent with ILPV after interventions. Our interventions improved anesthesia provider adherence to low tidal volume ILPV. IBW was found to be an important factor related to provider adherence to ILPV. Provider attitudes about their knowledge and practice consistent with ILPV also changed with our interventions.
Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sens... more Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Pl...
Pflugers Archiv : European journal of physiology, Feb 20, 2016
Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. H... more Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A ...
High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pa... more High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced incr...
In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal s... more In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal spontaneous activity of myelinated sensory neurons occurs early and is essential for establishing pain behaviors and other pathologies. Sympathetic sprouting into the dorsal root ganglion (DRG) is observed after SNL, and sympathectomy reduces pain behavior. Sprouting and spontaneous activity may be mutually reinforcing: blocking neuronal activity reduces sympathetic sprouting, and sympathetic spouts functionally increase spontaneous activity in vitro. However, most studies in this field have used nonspecific methods to block spontaneous activity, methods that also block evoked and normal activity. In this study, we injected small inhibitory (si) RNA directed against the NaV1.6 sodium channel isoform into the DRG before SNL. This isoform can mediate high-frequency repetitive firing, like that seen in spontaneously active neurons. Local knockdown of NaV1.6 markedly reduced mechanical pain b...
Sheng li xue bao : [Acta physiologica Sinica], Jan 25, 2008
Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persi... more Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persistent pathophysiological pain states. It has been well-documented that, after peripheral nerve injury or inflammation, functional and anatomical alterations sweep over the entire peripheral nervous system including the peripheral nerve endings, the injured or inflamed afferent fibers, the dorsal root ganglion (DRG), and the central afferent terminals in the spinal cord. Among all the changes, ectopic discharge or spontaneous activity of primary sensory neurons is of great clinical interest, as such discharges doubtless contribute to the development of pathological pain states such as neuropathic pain. Two key sources of abnormal spontaneous activity have been identified following peripheral nerve injury: the injured afferent fibers (neuroma) leading to the DRG, and the DRG somata. The purpose of this review is to provide a global account of the abnormal spontaneous activity in various an...
The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans... more The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finall...
Intraoperative lung-protective ventilation (ILPV) is defined as tidal volumes <8 mL/kg ide... more Intraoperative lung-protective ventilation (ILPV) is defined as tidal volumes <8 mL/kg ideal bodyweight and is increasingly a standard of care for major abdominal surgical procedures performed under general anesthesia. In this study, we report the result of a quality improvement initiative targeted at improving adherence to ILPV guidelines in a large academic teaching hospital. We performed a time-series study to determine whether anesthesia provider adherence to ILPV was affected by certain improvement interventions and patient ideal body weight (IBW). Tidal volume data were collected at 3 different time points for 191 abdominal surgical cases from June 2014 through April 2015. Improvement interventions during that period included education at departmental grand rounds, creation of a departmental ILPV policy, feedback of tidal volume and failure rate data at grand rounds sessions, and reducing default ventilator settings for tidal volume. Mean tidal volume per kilogram of ideal body weight (VT/kg IBW) and rates of noncompliance with ILPV were analyzed before and after the interventions. A survey was administered to assess provider attitudes after implementation of improvement interventions. Responses before and after interventions and between physician and nonphysician providers were analyzed. Reductions in mean VT/kg IBW and rates of failure for providers to use ILPV occurred after improvement interventions. Patients with IBW <65 kg received higher VT/kg IBW and had higher rates of failure to use ILPV than patients with IBW >65 kg. Surveyed providers demonstrated stronger agreement to having knowledge and practice consistent with ILPV after interventions. Our interventions improved anesthesia provider adherence to low tidal volume ILPV. IBW was found to be an important factor related to provider adherence to ILPV. Provider attitudes about their knowledge and practice consistent with ILPV also changed with our interventions.
Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sens... more Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Pl...
Pflugers Archiv : European journal of physiology, Feb 20, 2016
Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. H... more Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A ...
High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pa... more High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced incr...
In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal s... more In the spinal nerve ligation (SNL) model of neuropathic pain, as in other pain models, abnormal spontaneous activity of myelinated sensory neurons occurs early and is essential for establishing pain behaviors and other pathologies. Sympathetic sprouting into the dorsal root ganglion (DRG) is observed after SNL, and sympathectomy reduces pain behavior. Sprouting and spontaneous activity may be mutually reinforcing: blocking neuronal activity reduces sympathetic sprouting, and sympathetic spouts functionally increase spontaneous activity in vitro. However, most studies in this field have used nonspecific methods to block spontaneous activity, methods that also block evoked and normal activity. In this study, we injected small inhibitory (si) RNA directed against the NaV1.6 sodium channel isoform into the DRG before SNL. This isoform can mediate high-frequency repetitive firing, like that seen in spontaneously active neurons. Local knockdown of NaV1.6 markedly reduced mechanical pain b...
Sheng li xue bao : [Acta physiologica Sinica], Jan 25, 2008
Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persi... more Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persistent pathophysiological pain states. It has been well-documented that, after peripheral nerve injury or inflammation, functional and anatomical alterations sweep over the entire peripheral nervous system including the peripheral nerve endings, the injured or inflamed afferent fibers, the dorsal root ganglion (DRG), and the central afferent terminals in the spinal cord. Among all the changes, ectopic discharge or spontaneous activity of primary sensory neurons is of great clinical interest, as such discharges doubtless contribute to the development of pathological pain states such as neuropathic pain. Two key sources of abnormal spontaneous activity have been identified following peripheral nerve injury: the injured afferent fibers (neuroma) leading to the DRG, and the DRG somata. The purpose of this review is to provide a global account of the abnormal spontaneous activity in various an...
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Papers by Judith Strong