Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is though... more Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is thought to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial (SPB) neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.
How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals tran... more How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can direct AP firing in nociceptor as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory pro...
The central projections of axotomized fibers were assessed to investigate how well these matched ... more The central projections of axotomized fibers were assessed to investigate how well these matched the modality of the reinnervated receptor. Our results using intrafiber injection of horseradish peroxidase (HRP) and cord dorsum potentials evoked by intracellular stimulation of single afferents indicate that regenerating fibers can innervate inappropriate receptors. Mismatches included: (i) reinnervation of muscle receptors by cutaneous afferents, and vice versa; (ii) reinnervation of low threshold cutaneous receptors by nociceptive afferents; and (iii) reinnervation of slowly adapting receptors by fibers normally supplying rapidly adapting receptors.
Background: Previous studies have shown that the TRPV1 ion channel plays a critical role in the d... more Background: Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1−/− mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. Results: In wildtype mice we found that polymodal C-fibers (CPMs) lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs) were not sensitized following inflammation. However, results suggested that some...
P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in periphe... more P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in peripheral sensory neurons. Using ratiometric calcium imaging of isolated dorsal root ganglion neurons, we found that the majority of neurons responding to adenosine diphosphate, the preferred endogenous ligand, bound the lectin IB4 and expressed the ATP-gated ion channel P2X3. These neurons represent the majority of epidermal afferents in hairy skin, and are predominantly C-fiber polymodal nociceptors (CPMs), responding to mechanical stimulation, heat and in some cases cold. To characterize the function of P2Y1 in cutaneous afferents, intracellular recordings from sensory neuron somata were made using an ex vivo preparation in which the hindlimb skin, saphenous nerve, DRG and spinal cord were dissected in continuum, and cutaneous receptive fields characterized using digitally-controlled mechanical and thermal stimuli in male wild type mice. In P2Y1-/- mice, CPMs showed a striking increase in m...
1. The tibial and sural nerves were transected and repaired in nine adult cats. The receptive fie... more 1. The tibial and sural nerves were transected and repaired in nine adult cats. The receptive field (RF) properties of dorsal horn neurons were examined at three different intervals (5-6, 9, or 12 mo) after axotomy. The properties examined included RF location, area, and modality convergence. In some cases, discrete areas of the cell's RF were stimulated electrically while the evoked cord dorsum potentials (CDPs) and any intracellularly recorded responses were simultaneously recorded. 2. At the shortest interval following reinnervation, the somatotopic organization in the affected areas of the dorsal horn was lost. Dorsal horn cells that received input primarily from regenerated fibers had large, low-threshold excitatory RFs that contained much of the reinnervated skin. Those cells with RFs restricted to a fraction of the reinnervated skin had significant components of their RFs on the foot dorsum supplied by intact fibers (i.e., superficial peroneal nerve). 3. At longer interva...
1. The dorsal horn lamina III-IV projections of 10 hindlimb nerves innervating most of the hindli... more 1. The dorsal horn lamina III-IV projections of 10 hindlimb nerves innervating most of the hindlimb have been studied in the cat using transganglionic transport of horseradish peroxidase (HRP). The somatotopic organization of whole cutaneous nerve projections was largely in register with the somatotopic organization of dorsal horn cells. That is, nerves projected to areas of dorsal horn where their innervation fields overlap the receptive fields of dorsal horn cells. 2. However, long-ranging projections were observed that were more extensive than predicted from the somatotopy of dorsal horn cells: these long-ranging projections may reflect the presence of normally ineffective synapses (synapses that do not cause postsynaptic discharge during receptive-field mapping of dorsal horn cells,) or a misconception of dorsal horn cell somatotopy in S2 and caudal segments, or the existence of a functionally separate cell group in ventral lamina IV and lamina V of these segments. 3. The cutane...
1. Intracellular recordings were made in the somata of dorsal root ganglion cells in the L7 or S1... more 1. Intracellular recordings were made in the somata of dorsal root ganglion cells in the L7 or S1 DRG in cats anesthetized with alpha-chloralose. The properties of the action potentials (amplitude, duration, peak rate of rise), duration of afterhyperpolarization (AHP), magnitude of inward rectification, and axonal conduction velocity were measured. The adequate stimulus was determined, and the extent to which these properties are correlated was investigated. 2. All cells with receptive fields could be classified as mechanoreceptors. Most cells with A-beta-axons (greater than 36 m/s) could be activated by gentle mechanical stimulation but a small minority with conduction velocity in the low end of the A-beta-range were nociceptors. Cells with A-delta-axons (2-36 m/s) innervated either the very sensitive Down hair follicles (D-hairs) or high-threshold mechanoreceptors (HTMRs). In addition a group of A-delta-fibers was found for which no receptive field could be described. Their spikes...
Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is though... more Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is thought to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial (SPB) neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.
How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals tran... more How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can direct AP firing in nociceptor as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory pro...
The central projections of axotomized fibers were assessed to investigate how well these matched ... more The central projections of axotomized fibers were assessed to investigate how well these matched the modality of the reinnervated receptor. Our results using intrafiber injection of horseradish peroxidase (HRP) and cord dorsum potentials evoked by intracellular stimulation of single afferents indicate that regenerating fibers can innervate inappropriate receptors. Mismatches included: (i) reinnervation of muscle receptors by cutaneous afferents, and vice versa; (ii) reinnervation of low threshold cutaneous receptors by nociceptive afferents; and (iii) reinnervation of slowly adapting receptors by fibers normally supplying rapidly adapting receptors.
Background: Previous studies have shown that the TRPV1 ion channel plays a critical role in the d... more Background: Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1−/− mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. Results: In wildtype mice we found that polymodal C-fibers (CPMs) lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs) were not sensitized following inflammation. However, results suggested that some...
P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in periphe... more P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in peripheral sensory neurons. Using ratiometric calcium imaging of isolated dorsal root ganglion neurons, we found that the majority of neurons responding to adenosine diphosphate, the preferred endogenous ligand, bound the lectin IB4 and expressed the ATP-gated ion channel P2X3. These neurons represent the majority of epidermal afferents in hairy skin, and are predominantly C-fiber polymodal nociceptors (CPMs), responding to mechanical stimulation, heat and in some cases cold. To characterize the function of P2Y1 in cutaneous afferents, intracellular recordings from sensory neuron somata were made using an ex vivo preparation in which the hindlimb skin, saphenous nerve, DRG and spinal cord were dissected in continuum, and cutaneous receptive fields characterized using digitally-controlled mechanical and thermal stimuli in male wild type mice. In P2Y1-/- mice, CPMs showed a striking increase in m...
1. The tibial and sural nerves were transected and repaired in nine adult cats. The receptive fie... more 1. The tibial and sural nerves were transected and repaired in nine adult cats. The receptive field (RF) properties of dorsal horn neurons were examined at three different intervals (5-6, 9, or 12 mo) after axotomy. The properties examined included RF location, area, and modality convergence. In some cases, discrete areas of the cell's RF were stimulated electrically while the evoked cord dorsum potentials (CDPs) and any intracellularly recorded responses were simultaneously recorded. 2. At the shortest interval following reinnervation, the somatotopic organization in the affected areas of the dorsal horn was lost. Dorsal horn cells that received input primarily from regenerated fibers had large, low-threshold excitatory RFs that contained much of the reinnervated skin. Those cells with RFs restricted to a fraction of the reinnervated skin had significant components of their RFs on the foot dorsum supplied by intact fibers (i.e., superficial peroneal nerve). 3. At longer interva...
1. The dorsal horn lamina III-IV projections of 10 hindlimb nerves innervating most of the hindli... more 1. The dorsal horn lamina III-IV projections of 10 hindlimb nerves innervating most of the hindlimb have been studied in the cat using transganglionic transport of horseradish peroxidase (HRP). The somatotopic organization of whole cutaneous nerve projections was largely in register with the somatotopic organization of dorsal horn cells. That is, nerves projected to areas of dorsal horn where their innervation fields overlap the receptive fields of dorsal horn cells. 2. However, long-ranging projections were observed that were more extensive than predicted from the somatotopy of dorsal horn cells: these long-ranging projections may reflect the presence of normally ineffective synapses (synapses that do not cause postsynaptic discharge during receptive-field mapping of dorsal horn cells,) or a misconception of dorsal horn cell somatotopy in S2 and caudal segments, or the existence of a functionally separate cell group in ventral lamina IV and lamina V of these segments. 3. The cutane...
1. Intracellular recordings were made in the somata of dorsal root ganglion cells in the L7 or S1... more 1. Intracellular recordings were made in the somata of dorsal root ganglion cells in the L7 or S1 DRG in cats anesthetized with alpha-chloralose. The properties of the action potentials (amplitude, duration, peak rate of rise), duration of afterhyperpolarization (AHP), magnitude of inward rectification, and axonal conduction velocity were measured. The adequate stimulus was determined, and the extent to which these properties are correlated was investigated. 2. All cells with receptive fields could be classified as mechanoreceptors. Most cells with A-beta-axons (greater than 36 m/s) could be activated by gentle mechanical stimulation but a small minority with conduction velocity in the low end of the A-beta-range were nociceptors. Cells with A-delta-axons (2-36 m/s) innervated either the very sensitive Down hair follicles (D-hairs) or high-threshold mechanoreceptors (HTMRs). In addition a group of A-delta-fibers was found for which no receptive field could be described. Their spikes...
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Papers by H. Koerber