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J Quevedo - One of the best experts on this subject based on the ideXlab platform.
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The activation of D2 and D3 receptor subtypes inhibits pathways mediating Primary Afferent Depolarization (PAD) in the mouse spinal cord.
Neuroscience Letters, 2020Co-Authors: Jonathan J. Milla-cruz, Shawn Hochman, Elvia Mena-avila, Jorge R. Calvo, Carlos M. Villalón, J QuevedoAbstract:Abstract Somatosensory information can be modulated at the spinal cord level by Primary Afferent Depolarization (PAD), known to produce presynaptic inhibition (PSI) by decreasing neurotransmitter release through the activation of presynaptic ionotropic receptors. Descending monoaminergic systems also modulate somatosensory processing. We investigated the role of D1-like and D2-like receptors on pathways mediating PAD in the hemisected spinal cord of neonatal mice. We recorded low-threshold evoked dorsal root potentials (DRPs) and population monosynaptic responses as extracellular field potentials (EFPs). We used a paired-pulse conditioning-test protocol to assess homosynaptic and heterosynaptic depression of evoked EFPs to discriminate between dopaminergic effects on Afferent synaptic efficacy and/or on pathways mediating PAD, respectively. DA (10 μM) depressed low-threshold evoked DRPs by 43 %, with no effect on EFPs. These depressant effects on DRPs were mimicked by the D2-like receptor agonist quinpirole (35 %). Moreover, by using selective antagonists at D2-like receptors (encompassing the D2, D3, and D4 subtypes), we found that the D2 and D3 receptor subtypes participate in the quinpirole depressant inhibitory effects of pathways mediating PAD.
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serotonin dopamine and noradrenaline adjust actions of myelinated Afferents via modulation of presynaptic inhibition in the mouse spinal cord
PLOS ONE, 2014Co-Authors: David L Garciaramirez, Shawn Hochman, Jorge R. Calvo, J QuevedoAbstract:Gain control of Primary Afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including Primary Afferent Depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of Afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on Afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle Afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous Afferent-evoked responses, supporting a global modulation of the multimodal Afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal Afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated Afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors.
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presynaptic inhibition of Primary Afferents by Depolarization observations supporting nontraditional mechanisms
Annals of the New York Academy of Sciences, 2010Co-Authors: Shawn Hochman, Jacob Shreckengost, Hiroshi Kimura, J QuevedoAbstract:: Primary Afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all Primary Afferent fibers. A major mechanism producing Afferent PSI is via a channel-mediated Depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this Primary Afferent Depolarization (PAD) of low-threshold Afferents is mediated by minimally trisynaptic pathways with pharmacologically identified GABAergic interneurons forming last-order axo-axonic synapses onto Afferent terminals. There is still no "squeaky clean" evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABA(A) receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from Primary Afferents.
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Differential modulation of Primary Afferent Depolarization of segmental and ascending intraspinal collaterals of single muscle Afferents in the cat spinal cord.
Experimental Brain Research, 2004Co-Authors: Pablo Rudomín, Joel Lomelí, J QuevedoAbstract:We examined Primary Afferent Depolarization (PAD) in the anesthetized cat elicited in 109 pairs of intraspinal collaterals of single group I Afferents from the gastrocnemius nerve, one of the pair ending in the L3 segment, around the Clarke's column nuclei, and the other in the L6 segment within the intermediate zone. Tests for refractoriness were made to assess whether the responses produced by intraspinal stimulation in the L3 and L6 segments were due to activation of collaterals of the same Afferent fiber. PAD in each collateral was estimated by independent computer-controlled measurement of the intraspinal current required to maintain a constant probability of antidromic firing. In most fibers, stimulation of the ipsilateral posterior biceps and semitendinosus (PBSt) nerve with trains of pulses maximal for group I Afferents had a qualitatively similar effect but produced a larger PAD in the L6 than in the L3 collaterals. Stimulation of cutaneous nerves (sural and superficial peroneus) with single pulses and of the posterior articular nerve, the ipsilateral reticular formation, nucleus raphe magnus and contralateral motor cortex with trains of pulses often had qualitatively different effects. They could produce PAD and/or facilitate the PBSt-induced PAD in one collateral, and produce PAH and/or inhibit the PAD in the other collateral. These patterns could be changed in a differential manner by sensory or supraspinal conditioning stimulation. In summary, the present investigation suggests that the segmental and ascending collaterals of individual Afferents are not fixed routes for information transmission, but parts of dynamic systems in which information transmitted to segmental reflex pathways and to Clarke's column neurons by common sources can be decoupled by sensory and descending inputs and funneled to specific targets according to the motor tasks to be performed.
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Selective cortical and segmental control of Primary Afferent Depolarization of single muscle Afferents in the cat spinal cord
Experimental Brain Research, 1997Co-Authors: J R Eguibar, J Quevedo, Pablo RudomínAbstract:&p.1: This study was primarily aimed at investigating the selectivity of the cortico-spinal actions exerted on the pathways mediating Primary Afferent Depolarization (PAD) of muscle spindle and tendon organ Afferents ending within the intermediate nucleus at the L6‐L7 segmental level. To this end we analyzed, in the anesthetized cat, the effects produced by electrical stimulation of sensory nerves and of the cerebral cortex on (a) the intraspinal threshold of pairs of single group I Afferent fibers belonging to the same or to different hindlimb muscles and (b) the intraspinal threshold of two collaterals of the same muscle Afferent fiber. Afferent fibers were classified in three categories, according to the effects produced by stimulation of segmental nerves and of the cerebral cortex. Twenty-five of 40 fibers (62.5%) were depolarized by stimulation of group I posterior biceps and semitendinosus (PBSt) or tibialis (Tib) fibers, but not by stimulation of the cerebral cortex or of cutaneous and joint nerves, which instead inhibited the PBSt- or Tib-induced PAD (type A PAD pattern, usually seen in Ia fibers). The remaining 15 fibers (37.5%) were all depolarized by stimulation of the PBSt or Tib nerves and the cerebral cortex. Stimulation of cutaneous and joint nerves produced PAD in 10 of those 15 fibers (type B PAD pattern) and inhibited the PBSt- or Tib-induced PAD in the 5 remaining fibers (type C PAD pattern). Fibers with a type B or C PAD pattern are likely to be Ib. Not all sites in the cerebral cortex inhibited with the same effectiveness the segmentally induced PAD of group I fibers with a type A PAD pattern. With the weakest stimulation of the cortical surface, the most effective sites that inhibited the PAD of individual fibers were surrounded by less effective sites, scattered all along the motor cortex (area 4 γ and 6) and sensory cortex (areas 3, 2 and 1), far beyond the area of projection of group I fibers from the hindlimb. With higher strengths of cortical stimulation, the magnitude of the inhibition was also increased, and previously ineffective or weakly effective sites became more effective. Maps obtained when using the weakest cortical stimuli have indicated that the most effective regions that produced PAD of group I fibers with a type B or type C PAD pattern were also scattered throughout the sensory-motor cortex, in the same general area as those that inhibited the PAD of group I Afferents with a type A PAD pattern. In eight fibers with a type A PAD pattern it was possible to examine the intraspinal threshold of two collaterals of the same single Afferent fiber ending within the intermediate nucleus at the L7 segmental level. In six fibers, stimulation of the PBSt nerve with trains of pulses between 1.5 and 1.86 times threshold (◊T) produced a larger PAD in one collateral than in the other. In seven fibers, stimulation of the sensory-motor cortex and of cutaneous nerves produced a larger inhibition of the PBStinduced PAD in one collateral than in the other. The ratio of the cortically induced inhibition of the PAD elicited in the two collaterals could be modified by changing the strength of cortical and of PBSt stimulation. In three fibers it was possible to inhibit almost completely the background PAD elicited in one collateral while having little or no effect on the PAD in the other collateral. Changes in the intraspinal threshold of pairs of collaterals following electrical stimulation of segmental nerves and of the somato-sensory cortex were examined in three fibers with a type B and two fibers with a type C PAD pattern. In four fibers the PAD elicited by stimulation of cutaneous (4‐20◊T) and muscle nerves (1.54‐3.7◊T), or by stimulation of the sensory-motor cortex, was of different magnitude in the two collaterals. In two experiments it was possible to find cortical sites in which weak surface stimulation produced PAD in one collateral only. The magnitude of the PAD elicited in pairs of collaterals of group I Afferents with a type B or C PAD pattern, or the inhibition of the PAD in pairs of collaterals of fibers with a type A PAD pattern, appeared not to be topographically related to the site of spinal projection of the
P. Rudomin - One of the best experts on this subject based on the ideXlab platform.
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chapter 9 selectivity of presynaptic inhibition a mechanism for independent control of information flow through individual collaterals of single muscle spindle Afferents
Progress in Brain Research, 1999Co-Authors: P. RudominAbstract:Publisher Summary This chapter discusses the observations on the concept of the intraspinal arborizations of Afferent fibers that are not obligatory routes for the conduction of action potentials but are instead dynamic systems that can be modified by central mechanisms to restrict information to selected neuronal targets. The differential inhibition of Primary Afferent Depolarization (PAD) is envisaged as a means by which different spinal postsynaptic targets coupled by sensory input from a common source could be decoupled by central control mechanisms. This could be of relevance for motor performance and sensory discrimination. The extent to which these changes are reflected at the population level depends on the degree of synchronization of the PAD-mediating interneurons, a feature that can also be centrally controlled. A more functional approach to the understanding of the central mechanisms involved in the pre-synaptic control of information flow in sensory fibers will require the use of noninvasive methods in behaving animals performing specific motor tasks.
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Raphe magnus and reticulospinal actions on Primary Afferent Depolarization of group I muscle Afferents in the cat.
The Journal of physiology, 1995Co-Authors: J Quevedo, J R Eguibar, I Jiménez, P. RudominAbstract:1. In the anaesthetized cat, electrical stimulation of the bulbar reticular formation produced a short latency (2.1 +/- 0.3 ms) positive potential in the cord dorsum. In contrast, stimulation of the nucleus raphe magnus with strengths below 50 microA evoked a slow negative potential with a mean latency of 5.5 +/- 0.6 ms that persisted after sectioning the contralateral pyramid and was abolished by sectioning the ipsilateral dorsolateral funiculus. 2. The field potentials evoked by stimulation of the bulbar reticular formation and of the nucleus raphe magnus had a different intraspinal distribution, suggesting activation of different sets of segmental interneurones. 3. Stimulation of these two supraspinal nuclei produced Primary Afferent Depolarization (PAD) in single Ib fibres and inhibited the PAD elicited by group I volleys in single Ia fibres. The inhibition of the PAD of Ia fibres produced by reticulospinal and raphespinal inputs appears to be exerted on different interneurones along the PAD pathway. 4. It is concluded that, although reticulospinal and raphespinal pathways have similar inhibitory effects on PAD of Ia fibres, and similar excitatory effects on the PAD of Ib fibres, their actions are conveyed by partly independent pathways. This would allow their separate involvement in the control of posture and movement.
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Primary Afferent Depolarization of muscle Afferents elicited by stimulation of joint Afferents in cats with intact neuraxis and during reversible spinalization
Journal of Neurophysiology, 1993Co-Authors: J Quevedo, J R Eguibar, I Jiménez, R. F. Schmidt, P. RudominAbstract:1. In the anesthetized and artificially ventilated cat, stimulation of the posterior articular nerve (PAN) with low strengths (1.2-1.4 x T) produced a small negative response (N1) in the cord dorsum of the lumbosacral spinal cord with a mean onset latency of 5.2 ms. Stronger stimuli (> 1.4 x T) produced two additional components (N2 and N3) with longer latencies (mean latencies 7.5 and 15.7 ms, respectively), usually followed by a slow positivity lasting 100-150 ms. With stimulus strengths above 10 x T there was in some experiments a delayed response (N4; mean latency 32 ms). 2. Activation of posterior knee joint nerve with single pulses and intensities producing N1 responses only, usually produced no dorsal root potentials (DRPs), or these were rather small. Stimulation with strengths producing N2 and N3 responses produced distinct DRPs. Trains of pulses were clearly more effective than single pulses in producing DRPs, even in the low-intensity range. 3. Cooling the thoracic spinal cord to block impulse conduction, increased the DRPs and the N3 responses produced by PAN stimulation without significantly affecting the N2 responses. Reversible spinalization also increased the DRPs produced by stimulation of cutaneous nerves. In contrast, the DRPs produced by stimulation of group I Afferents from flexors were reduced. 4. Conditioning electrical stimulation of intermediate and high-threshold myelinated fibers in the PAN depressed the DRPs produced by stimulation of group I muscle and of cutaneous nerves. 5. Analysis of the intraspinal threshold changes of single Ia and Ib fibers has provided evidence that stimulation of intermediate and high threshold myelinated fibers in the posterior knee joint nerve inhibits the Primary Afferent Depolarization (PAD) of Ia fibers, and may either produce PAD or inhibit the PAD in Ib fibers, in the same manner as stimulation of cutaneous nerves. In 7/16 group I fibers the inhibition of the PAD was increased during reversible spinalization. 6. The results obtained suggest that intermediate and high-threshold myelinated fibers in the PAN have the same actions on Ia and Ib fibers as intermediate and high-threshold cutaneous Afferents and may therefore be considered as belonging to the same functional system. They further indicate that in anesthetized preparations the pathways mediating the PAD of group I fibers, as well as the pathways mediating the inhibition of the PAD, may be subjected to a descending control that is removed by spinalization.
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Reticulospinal actions on Primary Afferent Depolarization of cutaneous and muscle Afferents in the isolated frog neuraxis
Experimental Brain Research, 1993Co-Authors: Hortensia González, I Jiménez, P. RudominAbstract:The effects of the brainstem reticular formation on the intraspinal excitability of low threshold cutaneous and muscle Afferents were studied in the frog neuraxis isolated together with the right hindlimb nerves. Stimulation of low threshold fibers (less than two times threshold) in cutaneous nerves produced short latency, negative field potentials in the ipsilateral dorsal neuropil (200–400 μm depth) that reversed to positivity at deeper regions (500–700 μm). Stimulation of low threshold fibers (less than two times threshold) in muscle nerves produced, instead, negative responses that acquired their maximum amplitude in the ventral neuropil (700–900 μm depth). These electrophysiological findings suggest, in agreement with observations in the cat, that low threshold cutaneous and muscle Afferents end at different sites in the spinal cord. Intraspinal microstimulation applied within the dorsal neuropil produced antidromic responses in low threshold cutaneous Afferents that were increased in size following stimulation of the dorsal or ventral roots, as well as of the brainstem reticular formation. This increase in excitability is interpreted as being due to Primary Afferent Depolarization (PAD) of the intraspinal terminals of cutaneous fibers. Antidromic responses recorded in muscle nerves following intraspinal stimulation within the ventral neuropil were also increased following conditioning stimulation of adjacent dorsal or ventral roots. However, stimulation of the bulbar reticular formation produced practically no changes in the antidromic responses, but was able to inhibit the PAD of low threshold muscle Afferents elicited by stimulation of the dorsal or ventral roots. It is suggested that the PAD of low threshold cutaneous and muscle Afferents is mediated by independent sets of interneurons. Reticulospinal fibers would have excitatory connections with the interneurons mediating the PAD of cutaneous fibers and inhibitory connections with the interneurons mediating the PAD of muscle Afferents. Although our results provide no direct information on whether the reticulospinal depression of the PAD elicited in low threshold muscle Afferents is due to inhibition along the pathways producing PAD of muscle spindle or of tendon organ Afferents, it seems likely — by analogy with what has been seen in the cat spinal cord — that these inhibitory actions are mostly restricted to the pathways producing PAD in the terminal arborizations of muscle spindle Afferents. These results emphasize the specificity of the descending control of the synaptic efficacy of low threshold cutaneous and muscle Afferents which could be of importance for motor performance.
Pablo Rudomín - One of the best experts on this subject based on the ideXlab platform.
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Patterns of Primary Afferent Depolarization of segmental and ascending intraspinal collaterals of single joint Afferents in the cat
Experimental Brain Research, 2006Co-Authors: Pablo Rudomín, Joel LomelíAbstract:We have examined in the anesthetized cat the threshold changes produced by sensory and supraspinal stimuli on intraspinal collaterals of single Afferents from the posterior articular nerve (PAN). Forty-eight fibers were tested in the L3 segment, in or close to Clarke’s column, and 70 fibers in the L6–L7 segments within the intermediate zone. Of these, 15 pairs of L3 and L6–L7 collaterals were from the same Afferent. Antidromically activated fibers had conduction velocities between 23 and 74 m/s and peripheral thresholds between 1.1 and 4.7 times the threshold of the most excitable fibers (xT), most of them below 3 xT. PAN Afferents were strongly depolarized by stimulation of muscle Afferents and by cutaneous Afferents, as well as by stimulation of the bulbar reticular formation and the midline raphe nuclei. Stimulation of muscle nerves (posterior biceps and semitendinosus, quadriceps) produced a larger PAD (Primary Afferent Depolarization) in the L6–L7 than in the L3 terminations. Group II were more effective than group I muscle Afferents. As with group I muscle Afferents, the PAD elicited in PAN Afferents by stimulation of muscle nerves could be inhibited by conditioning stimulation of cutaneous Afferents. Stimulation of the cutaneous sural and superficial peroneal nerves increased the threshold of few terminations (i.e., produced Primary Afferent hyperpolarization, PAH) and reduced the threshold of many others, particularly of those tested in the L6–L7 segments. Yet, there was a substantial number of terminals where these conditioning stimuli had minor or no effects. Autogenetic stimulation of the PAN with trains of pulses increased the intraspinal threshold in 46% and reduced the threshold in 26% of fibers tested in the L6–L7 segments (no tests were made with trains of pulses on fibers ending in L3). These observations indicate that PAN Afferents have a rather small autogenetic PAD, particularly if this is compared with the effects of heterogenetic stimulation. Therefore, the depression of the PAN intraspinal fields produced by autogenetic stimulation described by Rudomin et al. (Exp Brain Res DOI 10.1007/s00221-006-0600-x, 2006) may be ascribed to other mechanisms besides a GABAa PAD. It is suggested that the small or no autogenetic PAD displayed by the examined joint Afferents prevents presynaptic filtering of their synaptic actions and preserves the original information generated in the periphery. This could be important for proper adjustment of limb position.
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Differential modulation of Primary Afferent Depolarization of segmental and ascending intraspinal collaterals of single muscle Afferents in the cat spinal cord.
Experimental Brain Research, 2004Co-Authors: Pablo Rudomín, Joel Lomelí, J QuevedoAbstract:We examined Primary Afferent Depolarization (PAD) in the anesthetized cat elicited in 109 pairs of intraspinal collaterals of single group I Afferents from the gastrocnemius nerve, one of the pair ending in the L3 segment, around the Clarke's column nuclei, and the other in the L6 segment within the intermediate zone. Tests for refractoriness were made to assess whether the responses produced by intraspinal stimulation in the L3 and L6 segments were due to activation of collaterals of the same Afferent fiber. PAD in each collateral was estimated by independent computer-controlled measurement of the intraspinal current required to maintain a constant probability of antidromic firing. In most fibers, stimulation of the ipsilateral posterior biceps and semitendinosus (PBSt) nerve with trains of pulses maximal for group I Afferents had a qualitatively similar effect but produced a larger PAD in the L6 than in the L3 collaterals. Stimulation of cutaneous nerves (sural and superficial peroneus) with single pulses and of the posterior articular nerve, the ipsilateral reticular formation, nucleus raphe magnus and contralateral motor cortex with trains of pulses often had qualitatively different effects. They could produce PAD and/or facilitate the PBSt-induced PAD in one collateral, and produce PAH and/or inhibit the PAD in the other collateral. These patterns could be changed in a differential manner by sensory or supraspinal conditioning stimulation. In summary, the present investigation suggests that the segmental and ascending collaterals of individual Afferents are not fixed routes for information transmission, but parts of dynamic systems in which information transmitted to segmental reflex pathways and to Clarke's column neurons by common sources can be decoupled by sensory and descending inputs and funneled to specific targets according to the motor tasks to be performed.
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Primary Afferent Depolarization produced in Aδ and C fibres by glutamate spillover? New ways to look at old things
The Journal of Physiology, 2000Co-Authors: Pablo RudomínAbstract:In 1957, Frank & Fuortes described a new mechanism for the regulation of the synaptic effectiveness of sensory fibres in the vertebrate spinal cord, namely presynaptic inhibition. However, it was not until the early sixties that Eccles and his collaborators related this inhibition to Primary Afferent Depolarization (PAD; for review see Rudomin & Schmidt, 1999). It is now fairly well established, from both electrophysiological and morphological investigations, that the terminal arborizations of large cutaneous and muscle Afferents in the vertebrate spinal cord are the targets of specific sets of GABAergic interneurones. Activation of GABAA receptors in the subsynaptic regions of the Afferent terminals increases their permeability to chloride ions and produces PAD. Presynaptic inhibition would result from the Depolarization produced by the outward chloride currents, as well as from increased membrane conductance, which may reduce, or prevent, conduction of action potentials at branch points within the intraspinal arborizations. There is in addition activation of GABAB receptors, which also reduces synaptic effectiveness without producing PAD (for review see Willis, 1998; Rudomin & Schmidt, 1999). In the mammalian spinal cord, PAD elicited in intraspinal branches from muscle spindles and tendon organs has a local character; namely, it may remain confined to some of the intraspinal collaterals of a single Afferent fibre, without spreading to nearby or distant collaterals of the same fibre (Lomeli et al. 1998). This allows, at least in principle, a functional decoupling of neuronal activity which may otherwise be correlated with common sensory inputs, as well as independent activation of specific sets of spinal neurones (see Rudomin & Schmidt, 1999). The observations of Russo et al. presented in this issue of The Journal of Physiology, show that in transverse slices of the isolated turtle spinal cord, the dorsal root potentials (DRPs) produced by supramaximal stimulation of dorsal roots are depressed, but not eliminated, after blockade of GABAA receptors; however, they are eliminated by additional blockade of NMDA and AMPA receptors. This suggests that glutamate may also be involved in the generation of DRPs. Other observations indicate that GABAA, NMDA and AMPA receptors may also contribute to the generation of a TTX-insensitive DRP. To the authors the most plausible explanation for these observations is that glutamate is released by action potentials conducted in Aδ and C Afferent fibres possessing TTX-insensitive sodium channels, and spills over onto the same and/or nearby Afferent terminals, where it produces PAD. To them, this non-spiking circuitry represents an effective way for the local regulation of transmitter release around active Primary Afferents in the same manner as has been found at hippocampal mossy fibre synapses (see Min et al. 1998). Clearly this is an attractive proposal, particularly because GABAergic axo-axonic synapses at central terminals of fine Afferent fibres are rare, at least in the spinal cord of higher vertebrates. Yet, C fibres in the dorsal horn are depolarized by activation of skin Afferents, suggesting volume-mediated autocrine and paracrine interactions (see Willis, 1998; Rudomin & Schmidt, 1999). At this stage, it seems important to determine whether the TTX-insensitive PAD is indeed due to the glutamate that is released by the stimulated fibres and spills over onto surrounding fibres, or whether it is due to accumulation of potassium ions in the extracellular space, released by the activated fibres, which may in turn induce glutamate release from neighbouring neuronal elements and glia. To the extent that the TTX-insensitive PAD is due to glutamate spillover, it should also be sensitive to changes affecting glutamate uptake and diffusion in the extracellular space (Min et al. 1998). This could be a relevant factor determining whether the spatial spread of glutamate remains confined within the environment of the activated Aδ and C fibres, or whether it also spreads to nearby inactive fibres, from muscle as well as from cutaneous Afferents. Another question that needs to be addressed, in order to pursue the proposal that glutamate spillover plays a significant role in the self-regulation of the synaptic effectiveness of the activated Afferents, is the extent to which the TTX-resistant PAD reduces transmitter release in fine Afferents. The observations of Russo et al. (2000) are consistent with the view that the Afferent terminals are not passive elements for information transmission, but rather are potential routes where information flow can be modulated by a variety of mechanisms. Those mediated by GABAA receptors appear to be highly selective, and could be largely involved in the execution of specific motor tasks and during sensory processing, while others, such as glutamate or potassium spillover, could form part of a more diffuse control system of synaptic efficacy in the same manner as other autocrine and paracrine interactions (see Rudomin & Schmidt, 1999, for review). It may be anticipated that the observations of Russo et al. (2000) will promote further investigation into self-regulatory mechanisms of synaptic efficacy in the vertebrate spinal cord, which although well documented for Aδ and C fibres in the mammalian spinal cord, could also be in operation in large muscle and cutaneous Afferents (Zytnicki & Jami, 1998).
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Selective cortical and segmental control of Primary Afferent Depolarization of single muscle Afferents in the cat spinal cord
Experimental Brain Research, 1997Co-Authors: J R Eguibar, J Quevedo, Pablo RudomínAbstract:&p.1: This study was primarily aimed at investigating the selectivity of the cortico-spinal actions exerted on the pathways mediating Primary Afferent Depolarization (PAD) of muscle spindle and tendon organ Afferents ending within the intermediate nucleus at the L6‐L7 segmental level. To this end we analyzed, in the anesthetized cat, the effects produced by electrical stimulation of sensory nerves and of the cerebral cortex on (a) the intraspinal threshold of pairs of single group I Afferent fibers belonging to the same or to different hindlimb muscles and (b) the intraspinal threshold of two collaterals of the same muscle Afferent fiber. Afferent fibers were classified in three categories, according to the effects produced by stimulation of segmental nerves and of the cerebral cortex. Twenty-five of 40 fibers (62.5%) were depolarized by stimulation of group I posterior biceps and semitendinosus (PBSt) or tibialis (Tib) fibers, but not by stimulation of the cerebral cortex or of cutaneous and joint nerves, which instead inhibited the PBSt- or Tib-induced PAD (type A PAD pattern, usually seen in Ia fibers). The remaining 15 fibers (37.5%) were all depolarized by stimulation of the PBSt or Tib nerves and the cerebral cortex. Stimulation of cutaneous and joint nerves produced PAD in 10 of those 15 fibers (type B PAD pattern) and inhibited the PBSt- or Tib-induced PAD in the 5 remaining fibers (type C PAD pattern). Fibers with a type B or C PAD pattern are likely to be Ib. Not all sites in the cerebral cortex inhibited with the same effectiveness the segmentally induced PAD of group I fibers with a type A PAD pattern. With the weakest stimulation of the cortical surface, the most effective sites that inhibited the PAD of individual fibers were surrounded by less effective sites, scattered all along the motor cortex (area 4 γ and 6) and sensory cortex (areas 3, 2 and 1), far beyond the area of projection of group I fibers from the hindlimb. With higher strengths of cortical stimulation, the magnitude of the inhibition was also increased, and previously ineffective or weakly effective sites became more effective. Maps obtained when using the weakest cortical stimuli have indicated that the most effective regions that produced PAD of group I fibers with a type B or type C PAD pattern were also scattered throughout the sensory-motor cortex, in the same general area as those that inhibited the PAD of group I Afferents with a type A PAD pattern. In eight fibers with a type A PAD pattern it was possible to examine the intraspinal threshold of two collaterals of the same single Afferent fiber ending within the intermediate nucleus at the L7 segmental level. In six fibers, stimulation of the PBSt nerve with trains of pulses between 1.5 and 1.86 times threshold (◊T) produced a larger PAD in one collateral than in the other. In seven fibers, stimulation of the sensory-motor cortex and of cutaneous nerves produced a larger inhibition of the PBStinduced PAD in one collateral than in the other. The ratio of the cortically induced inhibition of the PAD elicited in the two collaterals could be modified by changing the strength of cortical and of PBSt stimulation. In three fibers it was possible to inhibit almost completely the background PAD elicited in one collateral while having little or no effect on the PAD in the other collateral. Changes in the intraspinal threshold of pairs of collaterals following electrical stimulation of segmental nerves and of the somato-sensory cortex were examined in three fibers with a type B and two fibers with a type C PAD pattern. In four fibers the PAD elicited by stimulation of cutaneous (4‐20◊T) and muscle nerves (1.54‐3.7◊T), or by stimulation of the sensory-motor cortex, was of different magnitude in the two collaterals. In two experiments it was possible to find cortical sites in which weak surface stimulation produced PAD in one collateral only. The magnitude of the PAD elicited in pairs of collaterals of group I Afferents with a type B or C PAD pattern, or the inhibition of the PAD in pairs of collaterals of fibers with a type A PAD pattern, appeared not to be topographically related to the site of spinal projection of the
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Differential action of (-)-baclofen on the Primary Afferent Depolarization produced by segmental and descending inputs.
Experimental Brain Research, 1992Co-Authors: J Quevedo, J R Eguibar, I Jiménez, Pablo RudomínAbstract:The purpose of the present series of experiments was to analyze, in anesthetized and paralyzed cats, the effects of (-)-baclofen and picrotoxin on the Primary Afferent Depolarization (PAD) generated in single Ib Afferent fibers by either intraspinal microstimulation or stimulation of the segmental and descending pathways. PAD was estimated by recording dorsal root potentials and by measuring the changes in the intraspinal activation threshold of single Ib muscle Afferent fibers. The PAD elicited by stimulation of group I muscle or cutaneous Afferents was readily depressed and often abolished 20–40 min after the intravenous injection of 1–2 mg/kg (-)-baclofen. In contrast, the same amounts of (-)-baclofen produced a relatively small depression of the PAD elicited by stimulation of the brainstem reticular formation (RF). The monosynaptic PAD produced in single Ib fibers by intraspinal microstimulation within the intermediate nucleus was depressed and sometimes abolished following the i.v. injections of 1–2 mg/kg (-)-baclofen. Twenty to forty minutes after the i.v. injection of picrotoxin (0.5–1 mg/kg), there was a strong depression of the PAD elicited by stimulation of muscle and cutaneous Afferents as well as of the PAD produced by stimulation of the RF and the PAD produced by intraspinal microstimulation. The results obtained suggest that, in addition to its action on Primary Afferents, (-)-baclofen may depress impulse activity and/or transmitter release in a population of last-order GABAergic interneurons that mediate the PAD of Ib fibers. The existence of GABAb autoreceptors in last-order interneurons mediating the PAD may function as a self-limiting mechanism controlling the synaptic efficacy of these interneurons.
Shawn Hochman - One of the best experts on this subject based on the ideXlab platform.
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Activation of α-adrenoceptors depresses synaptic transmission of myelinated Afferents and inhibits pathways mediating Primary Afferent Depolarization (PAD) in the in vitro mouse spinal cord
Experimental Brain Research, 2020Co-Authors: Elvia Mena-avila, Shawn Hochman, Jonathan J. Milla-cruz, Jorge R. Calvo, Carlos M. Villalón, José-antonio Arias-montaño, Jorge N. QuevedoAbstract:Somatosensory Afferent transmission strength is controlled by several presynaptic mechanisms that reduce transmitter release at the spinal cord level. We focused this investigation on the role of α-adrenoceptors in modulating sensory transmission in low-threshold myelinated Afferents and in pathways mediating Primary Afferent Depolarization (PAD) of neonatal mouse spinal cord. We hypothesized that the activation of α-adrenoceptors depresses low threshold-evoked synaptic transmission and inhibits pathways mediating PAD. Extracellular field potentials (EFPs) recorded in the deep dorsal horn assessed adrenergic modulation of population monosynaptic transmission, while dorsal root potentials (DRPs) recorded at root entry zone assessed adrenergic modulation of PAD. We found that noradrenaline (NA) and the α_1-adrenoceptor agonists phenylephrine and cirazoline depressed synaptic transmission (by 15, 14 and 22%, respectively). DRPs were also depressed by NA, phenylephrine and cirazoline (by 62, 30, and 64%, respectively), and by the α_2-adrenoceptor agonist clonidine, although to a lower extent (20%). We conclude that NA depresses monosynaptic transmission of myelinated Afferents onto deep dorsal horn neurons via α_1-adrenoceptors and inhibits interneuronal pathways mediating PAD through the activation of α_1- and α_2-adrenoceptors. The functional significance of these modulatory actions in shaping cutaneous and muscle sensory information during motor behaviors requires further study.
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The activation of D2 and D3 receptor subtypes inhibits pathways mediating Primary Afferent Depolarization (PAD) in the mouse spinal cord.
Neuroscience Letters, 2020Co-Authors: Jonathan J. Milla-cruz, Shawn Hochman, Elvia Mena-avila, Jorge R. Calvo, Carlos M. Villalón, J QuevedoAbstract:Abstract Somatosensory information can be modulated at the spinal cord level by Primary Afferent Depolarization (PAD), known to produce presynaptic inhibition (PSI) by decreasing neurotransmitter release through the activation of presynaptic ionotropic receptors. Descending monoaminergic systems also modulate somatosensory processing. We investigated the role of D1-like and D2-like receptors on pathways mediating PAD in the hemisected spinal cord of neonatal mice. We recorded low-threshold evoked dorsal root potentials (DRPs) and population monosynaptic responses as extracellular field potentials (EFPs). We used a paired-pulse conditioning-test protocol to assess homosynaptic and heterosynaptic depression of evoked EFPs to discriminate between dopaminergic effects on Afferent synaptic efficacy and/or on pathways mediating PAD, respectively. DA (10 μM) depressed low-threshold evoked DRPs by 43 %, with no effect on EFPs. These depressant effects on DRPs were mimicked by the D2-like receptor agonist quinpirole (35 %). Moreover, by using selective antagonists at D2-like receptors (encompassing the D2, D3, and D4 subtypes), we found that the D2 and D3 receptor subtypes participate in the quinpirole depressant inhibitory effects of pathways mediating PAD.
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Serotonin, Dopamine and Noradrenaline Adjust Actions of Myelinated Afferents via Modulation of Presynaptic Inhibition in the Mouse Spinal Cord
2016Co-Authors: David L. Garcı́a-ramı́rez, Shawn Hochman, Jorge R. Calvo, Jorge N. QuevedoAbstract:Gain control of Primary Afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including Primary Afferent Depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of Afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on Afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle Afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 mM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous Afferent-evoked responses, supporting a global modulation of the multimodal Afferents stimulated. 5HT, DA and NA produced n
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serotonin dopamine and noradrenaline adjust actions of myelinated Afferents via modulation of presynaptic inhibition in the mouse spinal cord
PLOS ONE, 2014Co-Authors: David L Garciaramirez, Shawn Hochman, Jorge R. Calvo, J QuevedoAbstract:Gain control of Primary Afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including Primary Afferent Depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of Afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on Afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle Afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous Afferent-evoked responses, supporting a global modulation of the multimodal Afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal Afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated Afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors.
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stance phase force on the opposite limb dictates swing phase Afferent presynaptic inhibition during locomotion
Journal of Neurophysiology, 2012Co-Authors: Heather Hayes, Younghui Chang, Shawn HochmanAbstract:Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord–hindlimb preparation. We recorded lumbar dorsal root potentials to measure Primary Afferent Depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of Afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations.
Tony Priestley - One of the best experts on this subject based on the ideXlab platform.
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activation of spinal orl 1 receptors prevents acute cutaneous neurogenic inflammation role of nociceptin induced suppression of Primary Afferent Depolarization
Pain, 2002Co-Authors: Xiaowei Dong, P Williams, Yuping Jia, Tony PriestleyAbstract:AbstractNeurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory Afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the
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activation of spinal orl 1 receptors prevents acute cutaneous neurogenic inflammation role of nociceptin induced suppression of Primary Afferent Depolarization
Pain, 2002Co-Authors: Xiaowei Dong, P Williams, Yuping Jia, Tony PriestleyAbstract:Neurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory Afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the opioid receptor-like (ORL-1) G-protein coupled receptor, has been found to inhibit the local axon reflex-mediated neurogenic inflammation by suppressing the release of vasoactive neuropeptides from sensory Afferent terminals. The present study was to explore the role of spinal ORL-1 receptors in the modulation of DRR-induced neurogenic inflammation. We first examined the effect of nociceptin on DRR by recording dorsal root potentials (DRPs) and the associated antidromic discharges, evoked by electrical stimulation of an adjacent dorsal root in an in vitro neonatal rat spinal cord preparation. Nociceptin reversibly inhibited the DRP in a concentration-dependent manner (IC50: approximately 45 nM, maximal inhibition: approximately 50%), an effect that was antagonized by the ORL-1 receptor antagonist, J-113397. Neurochemical studies demonstrated that nociceptin (10 microM) also produced an approximately 40% reduction in gamma amino butyric acid (GABA) release evoked by electrical stimulation of neonatal rat spinal cord slices. On the other hand, nociceptin had no effect on exogenous GABA-evoked DRP. These findings suggest that the nociceptin-induced inhibition of the DRP is most likely due to the suppression of GABA release, the principle transmitter mediating DRP, from GABAergic neurons that are pre-synaptic to Primary Afferent terminals. Finally, in order to explore the physiological significance of such modulation in a fully integrated system, we evaluated the effect of intrathecally administered nociceptin on capsaicin-induced acute cutaneous neurogenic inflammation in rat hind paw, quantified by examining the degree of paw edema in anesthetized rats. The magnitude of capsaicin-induced increase of paw thickness was reduced by approximately 50% from 31+/-1.34% (n=6) to 15+/-1.63% (n=8; P<0.05) by nociceptin (10 micromol). We conclude that spinal ORL-1 receptors can modulate neurogenic inflammation by suppressing the GABAergic neuronal activity in the dorsal horn that is responsible for generating DRRs.