Activation Of Nociceptive Neurons Research Articles

The Role of Nociceptive Neurons in the Pathogenesis of Psoriasis.

Psoriasis is a chronic inflammatory skin disease. Emerging evidence shows that neurogenic inflammation, induced by nociceptive neurons and T helper 17 cell (Th17) responses, has a fundamental role in maintaining the changes in the immune system due to psoriasis. Nociceptive neurons, specific primary sensory nerves, have a multi-faceted role in detecting noxious stimuli, maintaining homeostasis, and regulating the immunity responses in the skin. Therefore, it is critical to understand the connections and interplay between the nociceptive neurons and the immune system in psoriasis. Here, we review works on the altered innervation that occurs in psoriasis. We examine how these distinct sensory neurons and their signal transducers participate in regulating inflammation. Numerous clinical studies report the dysfunction of nociceptive neurons in psoriasis. We discuss the mechanism behind the inconsistent activation of nociceptive neurons. Moreover, we review how neuropeptides, involved in regulating Th17 responses and the role of nociceptive neurons, regulate immunity in psoriasis. Understanding how nociceptive neurons regulate immune responses enhances our knowledge of the neuroimmunity involved in the pathogenesis of psoriasis and may form the basis for new approaches to treat it.

Sensory satellite glial Gq-GPCR activation alleviates inflammatory pain via peripheral adenosine 1 receptor activation

Glial fibrillary acidic protein expressing (GFAP+) glia modulate nociceptive neuronal activity in both the peripheral nervous system (PNS) and the central nervous system (CNS). Resident GFAP+ glia in dorsal root ganglia (DRG) known as satellite glial cells (SGCs) potentiate neuronal activity by releasing pro-inflammatory cytokines and neuroactive compounds. In this study, we tested the hypothesis that SGC Gq-coupled receptor (Gq-GPCR) signaling modulates pain sensitivity in vivo using Gfap-hM3Dq mice. Complete Freund’s adjuvant (CFA) was used to induce inflammatory pain, and mechanical sensitivity and thermal sensitivity were used to assess the neuromodulatory effect of glial Gq-GPCR activation in awake mice. Pharmacogenetic activation of Gq-GPCR signaling in sensory SGCs decreased heat-induced nociceptive responses and reversed inflammation-induced mechanical allodynia via peripheral adenosine A1 receptor activation. These data reveal a previously unexplored role of sensory SGCs in decreasing afferent excitability. The identified molecular mechanism underlying the analgesic role of SGCs offers new approaches for reversing peripheral nociceptive sensitization.

Capsaicin Functions as Drosophila Ovipositional Repellent and Causes Intestinal Dysplasia

Plants generate a plethora of secondary compounds (toxins) that potently influence the breadth of the breeding niches of animals, including Drosophila. Capsaicin is an alkaloid irritant from hot chili peppers, and can act as a deterrent to affect animal behaviors, such as egg laying choice. However, the mechanism underlying this ovipositional avoidance remains unknown. Here, we report that Drosophila females exhibit a robust ovipositional aversion to capsaicin. First, we found that females were robustly repelled from laying eggs on capsaicin-containing sites. Second, genetic manipulations show that the ovipositional aversion to capsaicin is mediated by activation of nociceptive neurons expressing the painless gene. Finally, we found that capsaicin compromised the health and lifespan of flies through intestinal dysplasia and oxidative innate immunity. Overall, our study suggests that egg-laying sensation converts capsaicin into an aversive behavior for female Drosophila, mirroring an adaptation to facilitate the survival and fitness of both parents and offspring.

The tuberculous tickle

Biomedicine Tuberculosis is caused by Mycobacterium tuberculosis (Mtb) and often manifests with a persistent cough. This cough is concerning not only for the patient but also because it provides a mechanism for onward transmission. Coughing often results from the activation of nociceptive neurons in the lungs. Ruhl et al. wanted to know how Mtb infection induces cough in patients. They isolated extracts from the bacterium and applied them to nociceptive neurons in vitro. A specific glycolipid, sulfolipid-1 (SL-1), activated the neurons and induced cough in guinea pigs, but Mtb mutants that did not synthesize SL-1 failed to induce cough in these animals. Thus, this bacterial molecule appears to specifically enhance transmissibility of Mtb. Cell 181 , 293 (2020).

MP07-13 REFRACTORY BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS

INTRODUCTION AND OBJECTIVE: Bladder pain syndrome/Interstitial cystitis (BPS/IC) as a pro-inflammatory chronic bladder state leads to functional changes in bladder afferent pathways like pain amplification, increased activity and recruitment of silent nociceptive neurons and sensitization of specific brain areas. Default Mode Network (DMN) is a set of regions activated during resting state, usually barred during specific tasks, reflecting the intrinsic activity of the brain. On the other hand, the sensorimotor network (SMN) plays a key role in structural neuroplasticity, usually present in chronic pain conditions. Our aim was to assess brain DMN and SMN in BPS/IC patients with and without noxious bladder stimuli using functional brain MRI (fMRI). METHODS: Six BPS/IC female patients, previously evaluated with a physical examination, bladder diary and bladder-pain related scores underwent 3 Tesla fMRI brain scanner. Acquisitions consisted of 10-minute blood oxygen level-dependent echo-planar imaging at rest. The first acquisition with an empty bladder state and a second one with suprapubic pain and/or bladder maximum capacity, after instillation of saline solution at room temperature, were performed. Data was processed based on the method of the independent component analysis using the MELODIC tool from Functional magnetic resonance imaging of the Brain Software Library (FSL). A semi-quantitative analysis was performed afterward. RESULTS: Patients mean age was 42.6 years (±5); mean VAS was 7±0.7; mean OSS was 24.8±1.9 mean day frequency and night frequency were 9.2±2.2 and 2.8±1.0 respectively; mean bladder maximum capacity was 260±54 ml and mean value for QoL (0-6) was 5±1. Four patients had Hunner’s lesions. All patients showed a comparable DMN activation in both empty and full bladder states and all of them presented a higher sensorimotor network (SMN) activation at an empty bladder state. There was no correlation between the presence of Hunners’ lesions and the pattern of network activity. CONCLUSIONS: Overlapping DMN activation at both empty and full bladder state, and consistently SMN deactivation with pain supports the relevant role of these networks in BPS/IC, as previously reported in other chronic pain syndromes.Source of Funding: None.

PAC1 receptor blockade reduces central nociceptive activity: new approach for primary headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed, and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near-maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the central nervous system suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.

PKCγ interneurons, a gateway to pathological pain in the dorsal horn.

Chronic pain is a frequent and disabling condition that is significantly maintained by central sensitization, which results in pathological amplification of responses to noxious and innocuous stimuli. As such, mechanical allodynia, or pain in response to a tactile stimulus that does not normally provoke pain, is a cardinal feature of chronic pain. Recent evidence suggests that the dorsal horn excitatory interneurons that express the γ isoform of protein kinase C (PKCγ) play a critical role in the mechanism of mechanical allodynia during chronic pain. Here, we review this evidence as well as the main aspects of the development, anatomy, electrophysiology, inputs, outputs, and pathophysiology of dorsal horn PKCγ neurons. Primary afferent high-threshold neurons transmit the nociceptive message to the dorsal horn of the spinal cord and trigeminal system where it activates second-order nociceptive neurons relaying the information to the brain. In physiological conditions, low-threshold mechanoreceptor inputs activate inhibitory interneurons in the dorsal horn, which may control activation of second-order nociceptive neurons. During chronic pain, low-threshold mechanoreceptor inputs now activate PKCγ neurons that forward the message to second-order nociceptive neurons, turning thus tactile inputs into pain. Several mechanisms may contribute to opening this gate, including disinhibition, activation of local astrocytes, release of diffusible factors such as reactive oxygen species, and alteration of the descending serotoninergic control on PKCγ neurons through 5-HT2A serotonin receptors. Dorsal horn PKCγ neurons, therefore, appear as a relevant therapeutic target to alleviate mechanical allodynia during chronic pain.

Эффекты стимуляции инфралимбической коры на реакции нейронов каудальной вентролатеральной ретикулярной формации, вызванные ноцицептивным раздражением толстой кишки крысы

The infralimbic cortex of the cerebral hemispheres is characterized by an extensive system of afferent and efferent connections with cortical, subcortical, bainstem structures and the spinal cord, which ensure its participation in the higher mechanisms of regulation of the functions of the visceral sphere. At the same time, the involvement of the infralimbic cortex in the mechanisms of cortical modulation of visceral nociception, both acute and chronic, seems to be poorly understood. In this work, using an experimental model of abdominal pain on two groups of urethane anesthetized rats (normal rats and rats with experimental colitis), we studied the effects of electrical stimulation of the infralimbic cortex on the neuronal (responses of neurons of the caudal ventrolateral reticular formation) and systemic (changes in arterial blood pressure) reactions induced by nociceptive distension of the colorectal region of colon. It has been found that in rats of both groups nociceptive colorectal distension was accompanied by both excitatory and inhibitory reactions of neurons of the ventrolateral reticular formation, as well as depressor changes in blood pressure. Electrical stimulation of the infralimbic cortex increased excitatory and decreased inhibitory neuronal responses to visceral painful stimulation and also enhanced nociceptive depressor responses in both normal rats and rats with colitis. This effect was more pronounced in the group of healthy animals. In general, the influence of the infralimbic cortex on nociceptive neurons of the ventrolateral reticular formation and vascular responses to visceral pain can be considered as facilitating visceral nociception. Quantitative differences in the effects of cortical stimulation in normal rats and rats with colitis are possibly related to differences in the brain processing of acute visceral pain and pain complicated by chronic inflammation. One of the possible mechanisms of cortical influence on visceral nociception may be modulation of the current activity of nociceptive neurons of the caudal ventrolateral reticular formation, directly or indirectly involved in the descending control of visceral pain.

P.185 Nx4 influences stress-induced activity of the anterior cingulate cortex and associated brain regions

The peripheral sympathetic nervous system consists of functionally distinct preganglionic-postganglionic channels that are involved in the regulation of various body functions by the brain. During nociception and pain the sympathetic systems are involved in the regulation of several reactions to protect the body tissues against injury from outside as well as from inside of the body. Under pathophysiological conditions such as tissue trauma with or without nerve lesion the sympathetic nervous system may be involved in the generation of pain and nociception. Now activity in the peripheral sympathetic neurons may lead to activation of nociceptive and non-nociceptive primary afferent neurons or may further inflammatory reactions which result in chronic pain. Multiple mechanisms underlie these pathophysiological processes.

Spicy Immunity: Pain to Gain

The skin is densely innervated with nociceptive neurons specialized in detecting noxious and painful stimuli. In a recent issue of Cell, Cohen etal. report that activation of cutaneous nociceptive neurons leads to a nerve-reflex action that is sufficient to provide a danger signal that triggers regional immunity to fight a microbial challenge.

The effectiveness of photobiomodulation in the management of temporomandibular pain sensitivity in rats: behavioral and neurochemical effects.

This study analyzed the effects of photobiomodulation (PBM) with low-level laser therapy on nociceptive behavior and neuronal activity in the trigeminal nucleus after experimental unilateral temporomandibular joint (TMJ) disc injury. The animals were divided into 4 groups (n = 10 each): group 1, surgical injury of the articular disc and PBM; group 2, sham-operated subjected to PBM; group 3, surgical injury of the articular disc; and group 4, control (Naïve). Ten sessions of PBM were performed using GaAs laser with a wavelength of 904nm, power of 75W pico, average power of 0.043W, area of the beam of 0.13cm2, duration of the pulses of 60nseg (in the frequency of 9500Hz), energy density of 5.95J/cm2, energy per point of 0.7J, and power density of 333.8mW/cm2, and the irradiation was done for 18s per point. Neuropathic symptoms were evaluated using the von Frey test. Trigeminal ganglion samples underwent immunoblotting to examine the expression of substance P, vanilloid transient potential receptor of subtype-1 (TRPV-1), and peptide related to the calcitonin gene (CGRP). There was a total decrease in pain sensitivity after the second session of PBM in operated animals, and this decrease remains until the last session. There was a significant decrease in the expression of SP, TRPV-1, and CGRP after PBM. Photobiomodulation therapy was effective in reducing nociceptive behavior and trigeminal nucleus neuronal activity after TMJ disc injury.

Inhibition of Muscular Nociceptive Afferents via the Activation of Cutaneous Nociceptors in a Rat Model of Inflammatory Muscle Pain.

Topical irritants such as capsaicin (CAP), peppermint oil (PO), and mustard oil (MO) are effective in relieving inflammatory muscle pain. We investigated the effects of topical irritants in a rat model of inflammatory muscle pain produced by injecting complete Freund's adjuvant (CFA) into the tibialis anterior muscle. CFA-induced mechanical hypersensitivity and the spontaneous activity of muscular nociceptive afferents, and decreased weight-bearing of the hindlimb were relieved by topical application of CAP, PO, or MO on the skin overlying the inflamed muscle. The effects of topical irritants were abolished when applied to the skin on the ipsilateral plantar region or on the contralateral leg, or when the relevant cutaneous nerve or dorsal root was transected. Our results demonstrated that topical irritants may alleviate inflammatory muscle pain via activating cutaneous nociceptors and subsequently inhibiting the abnormal activity of muscular nociceptive neurons.

Diverse Role of Biological Plasticity in Low Back Pain and Its Impact on Sensorimotor Control of the Spine.

Pain is complex. It is no longer acceptable to consider pain solely as a peripheral phenomenon involving activation of nociceptive neurons. The contemporary understanding of pain involves consideration of different underlying pain mechanisms and an increasing awareness of plasticity in all of the biological systems. Of note, recent advances in technology and understanding have highlighted the critical importance of neuroimmune interactions, both in the peripheral and central nervous systems, and the interaction between the nervous system and body tissues in the development and maintenance of pain, including low back pain (LBP). Further, the biology of many tissues changes when challenged by pain and injury, as reported in a growing body of literature on the biology of muscle, fat, and connective tissue. These advances in understanding of the complexity of LBP have implications for our understanding of pain and its interaction with the motor system, and may change how we consider motor control in the rehabilitation of LBP. This commentary provides a state-of-the-art overview of plasticity of biology in LBP. The paper is divided into 4 parts that address (1) biology of pain mechanisms, (2) neuroimmune interaction in the central nervous system, (3) neuroimmune interaction in the periphery, and (4) brain and peripheral tissue interaction. Each section considers the implications for clinical management of LBP. J Orthop Sports Phys Ther 2019;49(6):389-401. doi:10.2519/jospt.2019.8716.

(−)-α-Bisabolol reduces nociception and trigeminal central sensitisation in acute orofacial neuropathic pain induced by infraorbital nerve injury

Neuropathic orofacial pain conditions represent a challenge to diagnose and treat. Natural substances are promising therapeutic options for the control of pain. AimsThis study aimed to examine whether (−)-α-bisabolol (BISA), a natural terpene, can attenuate nociceptive behaviour and central sensitisation in a rodent model of trigeminal neuropathic pain. Materials and methodsInfraorbital nerve transection (IONX) or sham operation was performed in adult male rats. Head withdrawal thresholds as a measure of facial mechanical sensitivity were tested with von Frey monofilaments applied bilaterally to the facial vibrissal pad pre-operatively (baseline) and then post-operatively before and at 60, 120, 240 and 360 min after administration of vehicle control per oris (p.o.) or BISA (200 mg/kg p.o.) (n = 8/group). Effects of BISA or vehicle on the activity of nociceptive neurons recorded in the medullary dorsal horn (MDH) were tested on post - operative day 8–10. ANOVA followed by post-hoc Bonferroni tested for statistically significant differences (p < 0.05) across study groups and time points. Key findingsIONX animals (but not sham or naïve animals) showed post-operative facial mechanical hypersensitivity that was unaffected by vehicle. However, administration of BISA at post-operative day 7 significantly reversed the mechanical hypersensitivity in IONX rats; this effect lasted for at least 6 h. BISA also attenuated IONX-induced central sensitisation of MDH nociceptive neurons, as reflected in reversal of their reduced activation thresholds, increased responses to graded mechanical stimuli and enhanced spontaneous activity. SignificanceBISA may attenuate nociceptive behaviour and central sensitisation in a rat model of acute trigeminal neuropathic pain.

Chronic Headache in Children and Adolescents

Primary headache disorders such as migraine and tension-type headache begin as early as childhood or adolescence. Prevalence increases during primary school and adolescence. In tension-type headache, central pain sensitization and activation of central nociceptive neurons plays an important role. Migraine is a primary brain disorder with abnormalities in pain modulating systems and cortical stimulus processing. Bio-psycho-social factors play a decisive role in both types of headache. Secondary headaches due to an inflammatory or a structural brain alteration are rare. Diagnosis is based on clinical criteria. Typical recurrent headaches are diagnosed by patient's history and physical examination. In case of abnormalities, further diagnostic is needed. Treatment of tension-type headache is focused on multimodal pain therapy, treatment of migraine is focused on medication of attacks and secondary headaches need treatment of the underlying disease. Treatment goals are the reduction of pain perception, promotion of control and self-efficacy experiences, the increase of physical performance as well as the resumption of normal everyday structures and social contacts as a prerequisite for an increasing pain reduction.

Allatostatin C modulates nociception and immunity in Drosophila

Bacterial induced inflammatory responses cause pain through direct activation of nociceptive neurons, and the ablation of these neurons leads to increased immune infiltration. In this study, we investigated nociceptive-immune interactions in Drosophila and the role these interactions play during pathogenic bacterial infection. After bacterial infection, we found robust upregulation of ligand-gated ion channels and allatostatin receptors involved in nociception, which potentially leads to hyperalgesia. We further found that Allatostatin-C Receptor 2 (AstC-R2) plays a crucial role in host survival during infection with the pathogenic bacterium Photorhabdus luminescens. Upon examination of immune signaling in AstC-R2 deficient mutants, we demonstrated that Allatostatin-C Receptor 2 specifically inhibits the Immune deficiency pathway, and knockdown of AstC-R2 leads to overproduction of antimicrobial peptides related to this pathway and decreased host survival. This study provides mechanistic insights into the importance of microbe-nociceptor interactions during bacterial challenge. We posit that Allatostatin C is an immunosuppressive substance released by nociceptors or Drosophila hemocytes that dampens IMD signaling in order to either prevent immunopathology or to reduce unnecessary metabolic cost after microbial stimulation. AstC-R2 also acts to dampen thermal nociception in the absence of infection, suggesting an intrinsic neuronal role in mediating these processes during homeostatic conditions. Further examination into the signaling mechanisms by which Allatostatin-C alters immunity and nociception in Drosophila may reveal conserved pathways which can be utilized towards therapeutically targeting inflammatory pain and chronic inflammation.

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.

Metabotropic glutamate receptor subtype 7 in the dorsal striatum oppositely modulates pain in sham and neuropathic rats

The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N′-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum. Conversely, AMN082 inhibited pain and the activity of the ON cells while increased the activity of the OFF cells in rats with spared nerve injury (SNI) of the sciatic nerve. AMN082 also decreased glutamate levels in the dorsal striatum of SNI rats. The effect of AMN082 on mechanical allodynia and glutamate release was blocked by 6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydro-4(5H)-benzoxazolone (ADX71743), a selective mGluR7 negative allosteric modulator. Moreover, in the sham rats, AMN082 increased the activity of total nociceptive convergent neurons in the dorsal reticular nucleus while in the SNI rats, such activity was decreased. The administration of lidocaine into the subthalamic nucleus abolished the effect of AMN082 on the total nociceptive convergent neurons in the sham rats but not in the SNI rats. Thus, the dual effect of mGluR7 in facilitating or inhibiting pain responses may be due to the recruitment of different pathways of the basal ganglia, the indirect or direct pathway, in physiological or pathological conditions, respectively.

Mechanism of Activation of Enteric Nociceptive Neurons via Interaction of TLR4 and TRPV1 Receptors.

Evidence obtained by immunohistochemical double labeling and confocal laser scanning microscopy suggests that capsaicin, a ligand of the TRPV1 nociceptive vanilloid receptor, increases the number of TLR4-positive neurons in the rat colon myenteric plexus. In colitis caused by trinitrobenzene sulfonate, an increase in TRPV1 expression was more significant in both plexuses. Specific inhibitor of the TLR4 (C34) pattern-recognition receptor reduces TRPV1 expression in enteric neurons of both intact rats and rats with induced acute colitis. Thus, stimulation of nociceptive neurons by means of direct activation of their receptors of innate immunity (TLR4) is one of the possible mechanisms underlying the visceral pain in bacterial invasion and inflammatory bowel diseases.

Functional relationship between brainstem putative pain-facilitating neurons and spinal nociceptfive neurons during development of inflammation in rats

The so-called on- and off-cells of the rostral ventromedial medulla (RVM) send their axons to the spinal dorsal horn. Activation of on-cells precedes and coincides with a facilitation, and activation of off-cells coincides with an inhibition, of withdrawal reflexes elicited by noxious agents. Considerable evidence supports the notion that on- and off-cells modulate nocifensive reflexes during opioid and non-opioid action and also during normal circumstances and during peripheral neuropathy and inflammation. Yet it is unclear whether on- and off-cells act upon sensory spinal circuits that might lead to ascending projections and the experience of pain. Here, in deeply anesthetized rats we recorded single unit discharges from pairs of one on-like or off-like cell in RVM and a nociceptive neuron in the spinal dorsal horn with input from a hind paw. Both ongoing activity and responses to a calibrated noxious stimulus applied to the paw were documented during basal conditions and during development of paw inflammation. Probably due to the strong barbiturate anesthesia, off-like cells were depressed and did not yield interpretable results. However, we showed for the first time that during the increase in neuronal activity that results from paw inflammation the activity of spinal nociceptive neurons reflects the activity of their partner on-like cells in a highly correlated manner. This implies a tight relationship between spinal sensory and RVM modulatory functions that may underlie inflammation-induced hyperreflexia and clinically relevant hyperalgesia.