Contralateral Afferent Input to Lumbar Lamina I Neurons as a Neural Substrate for Mirror-Image Pain.

Mirror-image pain arises from pathologic alterations in the nociceptive processing network that controls functional lateralization of the primary afferent input. Although a number of clinical syndromes related to dysfunction of the lumbar afferent system are associated with the mirror-image pain, its morphophysiological substrate and mechanism of induction remain poorly understood. Therefore, we used ex vivo spinal cord preparation of young rats of both sexes to study organization and processing of the contralateral afferent input to the neurons in the major spinal nociceptive projection area Lamina I. We show that decussating primary afferent branches reach contralateral Lamina I, where 27% of neurons, including projection neurons, receive monosynaptic and/or polysynaptic excitatory drive from the contralateral Aδ-fibers and C-fibers. All these neurons also received ipsilateral input, implying their involvement in the bilateral information processing. Our data further show that the contralateral Aδ-fiber and C-fiber input is under diverse forms of inhibitory control. Attenuation of the afferent-driven presynaptic inhibition and/or disinhibition of the dorsal horn network increased the contralateral excitatory drive to Lamina I neurons and its ability to evoke action potentials. Furthermore, the contralateral Aßδ-fibers presynaptically control ipsilateral C-fiber input to Lamina I neurons. Thus, these results show that some lumbar Lamina I neurons are wired to the contralateral afferent system whose input, under normal conditions, is subject to inhibitory control. A pathologic disinhibition of the decussating pathways can open a gate controlling contralateral information flow to the nociceptive projection neurons and, thus, contribute to induction of hypersensitivity and mirror-image pain.SIGNIFICANCE STATEMENT We show that contralateral Aδ-afferents and C-afferents supply lumbar Lamina I neurons. The contralateral input is under diverse forms of inhibitory control and itself controls the ipsilateral input. Disinhibition of decussating pathways increases nociceptive drive to Lamina I neurons and may cause induction of contralateral hypersensitivity and mirror-image pain.

Presynaptic Interactions between Trigeminal and Cervical Nociceptive Afferents Supplying Upper Cervical Lamina I Neurons.

Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism, as they relay convergent nociceptive input to supraspinal pain centers. Unfortunately, little is known about the interactions between trigeminal and cervical afferents supplying Lamina I neurons. Here, we used rats of both sexes to show that cervical and trigeminal afferents interact via presynaptic inhibition, where monosynaptic inputs to Lamina I neurons undergo unidirectional as well as reciprocal presynaptic control. This means that afferent-driven presynaptic inhibition shapes the way trigeminal and cervical Aδ-fiber and C-fiber input reaches Lamina I projection neurons (PNs) and local-circuit neurons (LCNs). We propose that this inhibition provides a feedforward control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. As a consequence, disruption of the trigeminal and cervical afferent-driven presynaptic inhibition may contribute to development of primary headache syndromes.SIGNIFICANCE STATEMENT Cervical and trigeminal afferents innervate neighboring cranial territories, and their convergence on upper cervical dorsal horn neurons provides a potential substrate for pain referral in primary headache syndromes. Lamina I neurons are central to this mechanism as they relay convergent nociceptive input to supraspinal pain centers. Here, we show that cervical and trigeminal afferents interact via presynaptic inhibition, where inputs to Lamina I neurons undergo unidirectional as well as reciprocal control. The afferent-driven presynaptic inhibition shapes the trigeminocervical Aδ-fiber and C-fiber input to Lamina I neurons. This inhibition provides control of excitatory drive to Lamina I neurons that regulates their convergent and cervical-specific or trigeminal-specific processing modes. Disruption of this control may contribute to development of primary headache syndromes.

Facilitation of sensory transmission to motoneurons during cortical or sensory-evoked primary afferent depolarization (PAD) in humans.

Sensory and corticospinal tract (CST) pathways activate spinal GABAergic interneurons that have axoaxonic connections onto proprioceptive (Ia) afferents that cause long-lasting depolarizations (termed primary afferent depolarization, PAD). In rodents, sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia afferents, rather than at presynaptic terminals, and facilitates spike propagation to motoneurons by preventing branch-point failures, rather than causing presynaptic inhibition. We examined in 40 human participants whether putative activation of Ia-PAD by sensory or CST pathways can also facilitate Ia afferent activation of motoneurons via the H-reflex. H-reflexes in several leg muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar long-lasting time course (∼200 ms) to phasic PAD measured in rodent Ia afferents. Long trains of cutaneous or proprioceptive afferent conditioning produced longer-lasting facilitation of the H-reflex for up to 2 min, consistent with tonic PAD in rodent Ia afferents mediated by nodal α5-GABAA receptors for similar stimulation trains. Facilitation of H-reflexes by this conditioning was likely not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not alone facilitate the tonic firing rate of motor units. Furthermore, cutaneous conditioning increased the firing probability of single motor units (motoneurons) during the H-reflex without increasing their firing rate at this time, indicating that the underlying excitatory postsynaptic potential was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia afferent branches. KEY POINTS: Controlled execution of posture and movement requires continually adjusted feedback from peripheral sensory pathways, especially those that carry proprioceptive information about body position, movement and effort. It was previously thought that the flow of proprioceptive feedback from Ia afferents was only reduced by GABAergic neurons in the spinal cord that sent axoaxonic projections to the terminal endings of sensory axons (termed GABAaxo neurons). Based on new findings in rodents, we provide complementary evidence in humans to suggest that sensory and corticospinal pathways known to activate GABAaxo neurons that project to dorsal parts of the Ia afferent also increase the flow of proprioceptive feedback to motoneurons in the spinal cord. These findings support a new role for spinal GABAaxo neurons in facilitating afferent feedback to the spinal cord during voluntary or reflexive movements.

Post-activation depression from primary afferent depolarization (PAD) produces extensor H-reflex suppression following flexor afferent conditioning.

Suppression of the extensor H-reflex by flexor afferent conditioning is thought to be produced by a long-lasting inhibition of extensor Ia afferent terminals via GABAA receptor-activated primary afferent depolarization (PAD). Given the recent finding that PAD does not produce presynaptic inhibition of Ia afferent terminals, we examined in 28 participants if H-reflex suppression is instead mediated by post-activation depression of the extensor Ia afferents triggered by PAD-evoked spikes and/or by a long-lasting inhibition of the extensor motoneurons. A brief conditioning vibration of the flexor tendon suppressed both the extensor soleus H-reflex and the tonic discharge of soleus motor units out to 150 ms following the vibration, suggesting that part of the H-reflex suppression during this period was mediated by postsynaptic inhibition of the extensor motoneurons. When activating the flexor afferents electrically to produce conditioning, the soleus H-reflex was also suppressed but only when a short-latency reflex was evoked in the soleus muscle by the conditioning input itself. In mice, a similar short-latency reflex was evoked when optogenetic or afferent activation of GABAergic (GAD2+ ) neurons produced a large enough PAD to evoke orthodromic spikes in the test Ia afferents, causing post-activation depression of subsequent monosynaptic EPSPs. The long duration of this post-activation depression and related H-reflex suppression (seconds) was similar to rate-dependent depression that is also due to post-activation depression. We conclude that extensor H-reflex inhibition by brief flexor afferent conditioning is produced by both post-activation depression of extensor Ia afferents and long-lasting inhibition of extensor motoneurons, rather than from PAD inhibiting Ia afferent terminals. KEY POINTS: Suppression of extensor H-reflexes by flexor afferent conditioning was thought to be mediated by GABAA receptor-mediated primary afferent depolarization (PAD) shunting action potentials in the Ia afferent terminal. In line with recent findings that PAD has a facilitatory role in Ia afferent conduction, we show here that when large enough, PAD can evoke orthodromic spikes that travel to the Ia afferent terminal to evoke EPSPs in the motoneuron. These PAD-evoked spikes also produce post-activation depression of Ia afferent terminals and may mediate the short- and long-lasting suppression of extensor H-reflexes in response to flexor afferent conditioning. Our findings highlight that we must re-examine how changes in the activation of GABAergic interneurons and PAD following nervous system injury or disease affects the regulation of Ia afferent transmission to spinal neurons and ultimately motor dysfunction in these disorders.

Bumetanide increases postsynaptic inhibition after chronic SCI and decreases presynaptic inhibition with step-training.

Current anti-spastic medication significantly compromises motor recovery after spinal cord injury (SCI), indicating a critical need for alternative interventions. Because a shift in chloride homeostasis decreases spinal inhibition and contributes to hyperreflexia after SCI, we investigated the effect of bumetanide, an FDA-approved sodium-potassium-chloride intruder (NKCC1) antagonist, on presynaptic and postsynaptic inhibition. We compared its effect with step-training as it is known to improve spinal inhibition by restoring chloride homeostasis. In SCI rats, a prolonged bumetanide treatment increased postynaptic inhibition but not presynaptic inhibition of the plantar H-reflex evoked by posterior biceps and semitendinosus (PBSt) group I afferents. By using in vivo intracellular recordings of motoneurons, we further show that a prolonged bumetanide increased postsynaptic inhibition by hyperpolarizing the reversal potential for inhibitory postsynaptic potentials (IPSPs) after SCI. However, in step-trained SCI rats an acute delivery of bumetanide decreased presynaptic inhibition of the H-reflex, but not postsynaptic inhibition. These results suggest that bumetanide might be a viable option to improve postsynaptic inhibition after SCI, but it also decreases the recovery of presynaptic inhibition with step-training. We discuss whether the effects of bumetanide are mediated by NKCC1 or by off-target effects. KEY POINTS: After spinal cord injury (SCI), chloride homeostasis is dysregulated over time in parallel with the decrease in presynaptic inhibition of Ia afferents and postsynaptic inhibition of motoneurons, and the development of spasticity. While step-training counteracts these effects, it cannot always be implemented in the clinic because of comorbidities. An alternative intervention is to use pharmacological strategies to decrease spasticity without hindering the recovery of motor function with step-training. Here we found that, after SCI, a prolonged bumetanide (an FDA-approved antagonist of the sodium-potassium-chloride intruder, NKCC1) treatment increases postsynaptic inhibition of the H-reflex, and it hyperpolarizes the reversal potential for inhibitory postsynaptic potentials in motoneurons. However, in step-trained SCI, an acute delivery of bumetanide decreases presynaptic inhibition of the H-reflex, but not postsynaptic inhibition. Our results suggest that bumetanide has the potential to decrease spastic symptoms related to a decrease in postsynaptic but not presynaptic inhibition after SCI.

Regulation of primary afferent depolarization and homosynaptic post-activation depression during passive and active lengthening, shortening and isometric conditions.

PURPOSE: This study aimed to determine whether the modulation of primary afferent depolarization (PAD) and homosynaptic post-activation depression (HPAD) are involved in the lower efficacy of Ia-afferent-α-motoneuron transmission commonly observed during lengthening compared to isometric and shortening conditions. METHODS: 15 healthy young individuals participated in two experimental sessions dedicated to measurement in passive and active muscle states, respectively. In each session, PAD, HPAD and the efficacy of Ia-afferent-α-motoneuron transmission were evaluated during lengthening, shortening and isometric conditions. PAD was evaluated with D1 inhibition technique. Posterior tibial nerve stimulation was used to study HPAD and the efficacy of the Ia-afferent-α-motoneuron transmission through the recording of the soleus Hoffmann reflex (H reflex). RESULTS: PAD was increased in lengthening than shortening (11.2%) and isometric (12.3%) conditions regardless of muscle state (P < 0.001). HPAD was increased in lengthening than shortening (5.1%) and isometric (4.2%) conditions in the passive muscle state (P < 0.05), while no difference was observed in the active muscle state. H reflex was lower in lengthening than shortening (- 13.2%) and isometric (- 9.4%) conditions in both muscle states (P < 0.001). CONCLUSION: These results highlight the specific regulation of PAD and HPAD during lengthening conditions. However, the differences observed during passive lengthening compared to shortening and isometric conditions seem to result from an increase in Ia-afferent discharge, while the variations highlighted during active lengthening might come from polysynaptic descending pathways involving supraspinal centres that could regulate PAD mechanism.

Revisiting the use of Hoffmann reflex in motor control research on humans.

Research in movement science aims at unravelling mechanisms and designing methods for restoring and maximizing human functional capacity, and many techniques provide access to neural adjustments (acute changes) or long-term adaptations (chronic changes) underlying changes in movement capabilities. First described by Paul Hoffmann over a century ago, when an electrical stimulus is applied to a peripheral nerve, this causes action potentials in afferent axons, primarily the Ia afferents of the muscle spindles, which recruit homonymous motor neurons, thereby causing an electromyographic response known as the Hoffmann (H) reflex. This technique is a valuable tool in the study of the neuromuscular function in humans and has provided relevant information in the neural control of movement. The large use of the H reflex in motor control research on humans relies in part to its relative simplicity. However, such simplicity masks subtleties that require rigorous experimental protocols and careful data interpretation. After highlighting basic properties and methodological aspects that should be considered for the correct use of the H-reflex technique, this brief narrative review discusses the purpose of the H reflex and emphasizes its use as a tool to assess the effectiveness of Ia afferents in discharging motor neurones. The review also aims to reconsider the link between H-reflex modulation and Ia presynaptic inhibition, the use of the H-reflex technique in motor control studies, and the effects of ageing. These aspects are summarized as recommendations for the use of the H reflex in motor control research on humans.

Discrete field potentials produced by coherent activation of spinal dorsal horn neurons.

In addition to the action potentials generated by the ongoing activation of single dorsal horn neurons in the anesthetized cat, we often recorded small negative field potentials with a fast-rising phase and a slow decay (dIFPs). These potentials could be separated in different classes, each with a specific and rather constant shape and amplitude. They were largest in spinal laminae III-V and gradually faded at deeper locations, without showing the polarity reversal displayed at these depths by the focal potentials produced by stimulation of muscle and cutaneous afferents. We propose that the dIFPs are postsynaptic field potentials generated by strongly coupled sets of dorsal horn neurons displaying a spatial orientation that generates closed field potentials in response to stimulation of high-threshold cutaneous and muscle afferents. These neuronal sets could form part of the spinal inhibitory circuitry that mediates presynaptic inhibition and Ib non-reciprocal postsynaptic inhibition and could be involved in the sensory-motor transformations activated by stimulation of high-threshold cutaneous afferents.

Nicotinic receptor modulation of primary afferent excitability with selective regulation of Aδ-mediated spinal actions.

Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABAA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%-37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABAA receptor blockers and retained after tetrodotoxin block of voltage-gated Na+ channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents.NEW & NOTEWORTHY Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: 1) selective control of Aδ afferent transmission and 2) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.

Nociception induces a differential presynaptic modulation of the synaptic efficacy of nociceptive and proprioceptive joint afferents.

A previous study has indicated that during the state of central sensitization induced by the intradermic injection of capsaicin, there is a gradual facilitation of the dorsal horn neuronal responses produced by stimulation of the high-threshold articular afferents that is counteracted by a concurrent increase of descending inhibitory actions. Since these changes occurred without significantly affecting the responses produced by stimulation of the low-threshold articular afferents, it was suggested that the capsaicin-induced descending inhibition included a preferential presynaptic modulation of the synaptic efficacy of the slow conducting nociceptive joint afferents (Ramírez-Morales et al., Exp Brain Res 237:1629-1641, 2019). The present study was aimed to investigate more directly the contribution of presynaptic mechanisms in this descending control. We found that in the barbiturate anesthetized cat, stimulation of the high-threshold myelinated afferents in the posterior articular nerve (PAN) produces primary afferent hyperpolarization (PAH) in the slow conducting (25-35 m/s) and primary afferent depolarization (PAD) in the fast conducting (40-50 m/s) articular fibers. During the state of central sensitization induced by capsaicin, there is a supraspinally mediated shift of the autogenic PAH to PAD that takes place in the slow conducting fibers, basically without affecting the autogenic PAD generated in the fast conducting afferents. It is suggested that the change of presynaptic facilitation to presynaptic inhibition induced by capsaicin on the slow articular afferents is part of an homeostatic process aimed to keep the nociceptive-induced neuronal activity within manageable limits while preserving the proprioceptive information required for proper control of movement.

Modulation of the excitatory phase following the cutaneous silent period by vibration.

INTRODUCTION: The post-inhibition excitatory phase (E3) of the cutaneous silent period (CSP) is attributed to the resynchronization of motoneuron activity following the inhibitory period but there is also evidence that a somatosensory startle reflex may contribute to this phase. We hypothesized that the startle reflex component contained in E3 will decrease during vibration. METHODS: Sixteen healthy individuals were included in the study. CSP was recorded from slightly contracted right thenar muscles after painful index finger stimulation, before, during, and immediately after vibration. The values of the percentage change of E3 relative to pre-stimulus baseline (E3%) were compared before, during, and after vibration for each individual. RESULTS: There was a reduction in E3% during vibration and the values returned to normal immediately after vibration (153.1 ± 43.5%, 115.2 ± 30.2%, 154.9 ± 68.2%, respectively; p = 0.030). DISCUSSION: E3 is reduced during vibration in healthy individuals, presumably due to suppression of a reflex component, which is superimposed upon the known resynchronization of motoneurons.

Presynaptic inhibition in restless legs syndrome.

Introduction: Restless legs syndrome (RLS) is a condition that particularly urges at night in resting and causes the need to move the legs. Although the pathophysiology has not yet been clarified, dopamine and iron metabolism and spinal cord pathologies are blamed for causing the condition. There are few studies on spinal reflex mechanisms on RLS. In the present study, we aimed to investigate the role of presynaptic inhibition (PreI) in the spinal cord in RLS.Methods: Fourteen patients with RLS and 14 controls with similar demographic characteristics were included in the study. Soleus muscle H-reflex (Ht) investigation was performed for subjects whose electrophysiologic investigation was normal. The Ht response was conditioned to the stimulation of the common peroneal nerve (CPN) (Hc). The test and conditioned stimulation intervals were kept between 10 ms, 20 ms, 30 ms, 40 ms, 50 ms, 75 ms, 100 ms, 150 ms and 200 ms. In each inter-stimulus interval, nonparametric repeat measurement evaluations were conducted with the percentage value of Hc/Ht. The Hc/Ht values of the study and control groups in the same intervals were compared separately.Results: A significant decrease was detected in Hc values in the control group in the repeat measurement values at 20 ms and 100 ms inter-stimulus intervals; however, there was not decrease in any intervals in the patient's group.Conclusion: The absence of any decrease in Hc reflexes for 20-100 ms intervals revealed that discernible PreI was vanished in RLS patients.

Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits.

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.

Direct evidence for decreased presynaptic inhibition evoked by PBSt group I muscle afferents after chronic SCI and recovery with step-training in rats.

KEY POINTS: Presynaptic inhibition is modulated by supraspinal centres and primary afferents in order to filter sensory information, adjust spinal reflex excitability, and ensure smooth movement. After spinal cord injury (SCI), the supraspinal control of primary afferent depolarization (PAD) interneurons is disengaged, suggesting an increased role for sensory afferents. While increased H-reflex excitability in spastic individuals indicates a possible decrease in presynaptic inhibition, it remains unclear whether a decrease in sensory-evoked PAD contributes to this effect. We investigated whether the PAD evoked by hindlimb afferents contributes to the change in presynaptic inhibition of the H-reflex in a decerebrated rat preparation. We found that chronic SCI decreases presynaptic inhibition of the plantar H-reflex through a reduction in PAD evoked by posterior biceps-semitendinosus (PBSt) muscle group I afferents. We further found that step-training restored presynaptic inhibition of the plantar H-reflex evoked by PBSt, suggesting the presence of activity-dependent plasticity of PAD pathways activated by flexor muscle group I afferents. ABSTRACT: Spinal cord injury (SCI) results in the disruption of supraspinal control of spinal networks and an increase in the relative influence of afferent feedback to sublesional neural networks, both of which contribute to enhancing spinal reflex excitability. Hyperreflexia occurs in ∼75% of individuals with a chronic SCI and critically hinders functional recovery and quality of life. It is suggested that it results from an increase in motoneuronal excitability and a decrease in presynaptic and postsynaptic inhibitory mechanisms. In contrast, locomotor training decreases hyperreflexia by restoring presynaptic inhibition. Primary afferent depolarization (PAD) is a powerful presynaptic inhibitory mechanism that selectively gates primary afferent transmission to spinal neurons to adjust reflex excitability and ensure smooth movement. However, the effect of chronic SCI and step-training on the reorganization of presynaptic inhibition evoked by hindlimb afferents, and the contribution of PAD has never been demonstrated. The objective of this study is to directly measure changes in presynaptic inhibition through dorsal root potentials (DRPs) and its association with plantar H-reflex inhibition. We provide direct evidence that H-reflex hyperexcitability is associated with a decrease in transmission of PAD pathways activated by posterior biceps-semitendinosus (PBSt) afferents after chronic SCI. More precisely, we illustrate that the pattern of inhibition evoked by PBSt group I muscle afferents onto both L4-DRPs and plantar H-reflexes evoked by the distal tibial nerve is impaired after chronic SCI. These changes are not observed in step-trained animals, suggesting a role for activity-dependent plasticity to regulate PAD pathways activated by flexor muscle group I afferents.

Repeated and patterned stimulation of cutaneous reflex pathways amplifies spinal cord excitability.

Priming with patterned stimulation of antagonist muscle afferents induces modulation of spinal cord excitability as evidenced by changes in group Ia reciprocal inhibition. When assessed transiently with a condition-test pulse paradigm, stimulating cutaneous afferents innervating the foot reduces Ia presynaptic inhibition and facilitates soleus Hoffmann (H)-reflex amplitudes. Modulatory effects (i.e., priming) of longer lasting sensory stimulation of cutaneous afferents innervating the foot have yet to be examined. As a first step, we examined how priming with 20 min of patterned and alternating stimulation between the left and right foot affects spinal cord excitability. During priming, stimulus trains (550 ms; consisting of twenty-eight 1-ms pulses at 51 Hz, 1.2 times the radiating threshold) were applied simultaneously to the sural and plantar nerves of the ankle. Stimulation to the left and right ankle was out of phase by 500 ms. We evoked soleus H-reflexes and muscle compound action potentials (M waves) before and following priming stimulation to provide a proxy measure of spinal cord excitability. H-reflex and M-wave recruitment curves were recorded at rest, during brief (<2 min) arm cycling, and with sural conditioning [train of five 1-ms pulses at 2 times the radiating threshold (RT) with a condition-test interval (C-T) = 80 ms]. Data indicate an increase in H-reflex excitability following priming via patterned sensory stimulation. Transient sural conditioning was less effective following priming, indicating that the increased excitability of the H-reflex is partially attributable to reductions in group Ia presynaptic inhibition. Sensory stimulation to cutaneous afferents, which enhances spinal cord excitability, may prove useful in both rehabilitation and performance settings.NEW & NOTEWORTHY Priming via patterned stimulation of the nervous system induces neuroplasticity. Yet, accessing previously known cutaneous reflex pathways to alter muscle reflex excitability has not yet been examined. Here, we show that sensory stimulation of the cutaneous afferents that innervate the foot sole can amplify spinal cord excitability, which, in this case, is attributed to reductions in presynaptic inhibition.

Reviewing the case for compromised spinal inhibition in neuropathic pain.

A striking and debilitating property of the nervous system is that damage to this tissue can cause chronic intractable pain, which persists long after resolution of the initial insult. This neuropathic form of pain can arise from trauma to peripheral nerves, the spinal cord, or brain. It can also result from neuropathies associated with disease states such as diabetes, human immunodeficiency virus/AIDS, herpes, multiple sclerosis, cancer, and chemotherapy. Regardless of the origin, treatments for neuropathic pain remain inadequate. This continues to drive research into the underlying mechanisms. While the literature shows that dysfunction in numerous loci throughout the CNS can contribute to chronic pain, the spinal cord and in particular inhibitory signalling in this region have remained major research areas. This review focuses on local spinal inhibition provided by dorsal horn interneurons, and how such inhibition is disrupted during the development and maintenance of neuropathic pain.

Modulation of spinal cord excitability following remote limb ischemic preconditioning in healthy young men.

Remote limb ischemic preconditioning (RIPC) has shown to improve dynamic postural control in humans. However, studies on the underlying adaptations of spinal cord networks have never been performed. The present work addresses this issue by investigating parameters from the soleus H-reflex recruitment curve (RC), presynaptic mechanisms of reflex modulation (presynaptic inhibition-PSI, and post activation depression-PAD), and the excursion of the center of pressure (CP) recorded during 1 min in upright stance over a compliant surface. A sham ischemic protocol (partial obstruction of blood flow) was applied to the contralateral thigh along four consecutive days. The same procedure was repeated with full obstruction (RIPC) three days after ending the sham protocol. Data were collected before and after both sham and RIPC protocols. The follow-up data were collected five days after the last ischemic intervention. Significant reduction was detected for both the fast oscillations of the CP (higher frequency components) and the parameter estimated from the RC corresponding to the high amplitude H-reflexes (p < 0.05). Even though the magnitude of effects was similar, it was washed out within three days after sham, but persisted for at least five days after RIPC. No significant differences were found for PSI and PAD levels across conditions. These findings indicate that RIPC leads to enduring changes in spinal cord excitability for the latest reflexively recruited motoneurons, along with improvement in balance control. However, these adaptations were not mediated by the presynaptic mechanisms currently assessed.

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.

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 α1-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 α2-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 α1-adrenoceptors and inhibits interneuronal pathways mediating PAD through the activation of α1- and α2-adrenoceptors. The functional significance of these modulatory actions in shaping cutaneous and muscle sensory information during motor behaviors requires further study.

µ-Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid-induced hyperalgesia.

KEY POINTS: µ-Opioid receptors (MORs) are expressed peripherally and centrally, but the loci of MORs responsible for clinically relevant opioid analgesia are uncertain. Crossing Oprm1flox/flox and AdvillinCre/+ mice completely ablates MORs in dorsal root ganglion neurons and reduces the MOR expression level in the spinal cord. Presynaptic MORs expressed at primary afferent central terminals are essential for synaptic inhibition and potentiation of sensory input by opioids. MOR ablation in primary sensory neurons diminishes analgesic effects produced by systemic and intrathecal opioid agonists and abolishes chronic opioid treatment-induced hyperalgesia. These findings demonstrate a critical role of MORs expressed in primary sensory neurons in opioid analgesia and suggest new strategies to increase the efficacy and reduce adverse effects of opioids. ABSTRACT: The pain and analgesic systems are complex, and the actions of systemically administered opioids may be mediated by simultaneous activation of µ-opioid receptors (MORs, encoded by the Oprm1 gene) at multiple, interacting sites. The loci of MORs and circuits responsible for systemic opioid-induced analgesia and hyperalgesia remain unclear. Previous studies using mice in which MORs are removed from Nav1.8- or TRPV1-expressing neurons provided only an incomplete and erroneous view about the role of peripheral MORs in opioid actions in vivo. In the present study, we determined the specific role of MORs expressed in primary sensory neurons in the analgesic and hyperalgesic effects produced by systemic opioid administration. We generated Oprm1 conditional knockout (Oprm1-cKO) mice in which MOR expression is completely deleted from dorsal root ganglion neurons and substantially reduced in the spinal cord, which was confirmed by immunoblotting and immunocytochemical labelling. Both opioid-induced inhibition and potentiation of primary sensory input were abrogated in Oprm1-cKO mice. Remarkably, systemically administered morphine potently inhibited acute thermal and mechanical nociception and persistent inflammatory pain in control mice but had little effect in Oprm1-cKO mice. The analgesic effect of intrathecally administered morphine was also profoundly reduced in Oprm1-cKO mice. Additionally, chronic morphine treatment-induced hyperalgesia was absent in Oprm1-cKO mice. Our findings directly challenge the notion that clinically relevant opioid analgesia is mediated mostly by centrally expressed MORs. MORs in primary sensory neurons, particularly those expressed presynaptically at the first sensory synapse in the spinal cord, are crucial for both opioid analgesia and opioid-induced hyperalgesia.

Spinal plasticity with motor imagery practice.

KEY POINTS: While a consensus has now been reached on the effect of motor imagery (MI) - the mental simulation of an action - on motor cortical areas, less is known about its impact on spinal structures. The current study, using H-reflex conditioning paradigms, examined the effect of a 20 min MI practice on several spinal mechanisms of the plantar flexor muscles. We observed modulations of spinal presynaptic circuitry while imagining, which was even more pronounced following an acute session of MI practice. We suggested that the small cortical output generated during MI may reach specific spinal circuits and that repeating MI may increase the sensitivity of the spinal cord to its effects. The short-term plasticity induced by MI practice may include spinal network modulation in addition to cortical reorganization. ABSTRACT: Kinesthetic motor imagery (MI) is the mental simulation of a movement with its sensory consequences but without its concomitant execution. While the effect of MI practice on cortical areas is well known, its influence on spinal circuitry remains unclear. Here, we assessed plastic changes in spinal structures following an acute MI practice. Thirteen young healthy participants accomplished two experimental sessions: a 20 min MI training consisting of four blocks of 25 imagined maximal isometric plantar flexions, and a 20 min rest (control session). The level of spinal presynaptic inhibition was assessed by conditioning the triceps surae spinal H-reflex with two methods: (i) the stimulation of the common peroneal nerve that induced D1 presynaptic inhibition (HPSI response), and (ii) the stimulation of the femoral nerve that induced heteronymous Ia facilitation (HFAC response). We then compared the effects of MI on unconditioned (HTEST ) and conditioned (HPSI and HFAC ) responses before, immediately after and 10 min after the 20 min session. After resting for 20 min, no changes were observed on the recorded parameters. After MI practice, the amplitude of rest HTEST was unchanged, while HPSI and HFAC significantly increased, showing a reduction of presynaptic inhibition with no impact on the afferent-motoneuronal synapse. The current results revealed the acute effect of MI practice on baseline spinal presynaptic inhibition, increasing the sensitivity of the spinal circuitry to MI. These findings will help in understanding the mechanisms of neural plasticity following chronic practice.