Alfredo Ribeiro-da-Silva

McGill University | McGill · Department of Pharmacology and Therapeutics

Arthritis is the leading cause of musculoskeletal pain and disability worldwide. Nearly 50% of individuals over the age of 65 have arthritis, which contributes to limited function, articular pain, physical inactivity, and diminished quality of life. Therapeutic exercise is often recommended in clinical settings for patients experiencing arthritic p...

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firin...

Neuropathic pain is a debilitating condition resulting from damage to the nervous system. Imbalance of spinal excitation and inhibition has been proposed to contribute to neuropathic pain. However, the structural basis of this imbalance remains unknown. Using a preclinical model of neuropathic pain, we show that microglia selectively engulf spinal...

Spinal cord stimulation (SCS) reduces chronic pain. Conventional (40-60 Hz) SCS engages spinal inhibitory mechanisms by activating low-threshold mechanoreceptive afferents with axons in the dorsal columns (DCs). But activating DC axons typically causes a buzzing sensation (paresthesia) that can be uncomfortable. Kilohertz-frequency (1-10 kHz) SCS p...

The anterior cingulate cortex (ACC) processes the affective component of pain, whereas the primary somatosensory cortex (S1) is involved in its sensory-discriminative component. Injection of morphine in the ACC has been reported to be analgesic, and endogenous opioids in this area are required for pain relief. Mu opioid receptors (MOR) are expresse...

The GPCR SUCNR1/GPR91 exerts proangiogenesis upon stimulation with the Krebs cycle metabolite succinate. GPCR signaling depends on the surrounding environment and intracellular localization through location bias. Here, we show by microscopy and by cell fractionation that in neurons, SUCNR1 resides at the endoplasmic reticulum (ER), while being full...

The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very...

Activation of microglia in the spinal cord dorsal horn following peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that following peripheral nerve injury, microglia degrade extracellular matrix...

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability, and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activatio...

Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve inj...

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that periphe...

Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain unknown. Here, we show that peripheral...

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane a...

Introduction: Mast cell (MC) activation could establish a positive feedback loop that perpetuates inflammation and maintains pain. Stabilizing MCs with ketotifen fumarate (KF) may disrupt this loop and relieve pain. Objective: We aimed to test the effect of treatment with KF in pain assays in mice and in a case series of patients with chronic wi...

The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very...

Introduction: Osteoarthritis (OA)-associated pain is often poorly managed, as our understanding of the underlying pain mechanisms remains limited. The known variability from patient to patient in pain control could be a consequence of a neuropathic component in OA. Methods: We used a rat monoiodoacetate model of the ankle joint to study the time...

Objectives: Alterations beyond joint inflammation such as changes in dorsal horn (DH) excitability contribute to pain in inflammatory arthritis (IA). More complete understanding of specific underlying mechanisms will be important to define novel targets for the treatment of IA pain. Pre-clinical models are useful, but relevant pain assays are vital...

Itch and pain are distinct unpleasant sensations that can be triggered from the same receptive fields in the skin, raising the question of how pruriception and nociception are coded and discriminated. Here, we tested the multimodal capacity of peripheral first-order neurons, focusing on the genetically defined subpopulation of mouse C-fibers that e...

Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxica...

It is consistently reported that in inflammatory arthritis (IA) pain may continue despite well controlled inflammation, most likely due to interactions between joint pathology and pain pathway alterations. Nervous system alterations have been described but much remains to be understood about neuronal and central non-neuronal changes in inflammatory...

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elu...

Joint pain affects 1 in 5 adults in developed countries and, as there are currently no optimal treatments, the identification of novel therapeutic targets is needed. Although it is known that there is a sensitization in the pain pathways, the specific mechanisms remain poorly understood. A change that could alter pain pathway excitability is an ana...

Introduction/Aim: There is an imperfect correlation between joint changes and pain in arthritis, suggesting that there may be mechanisms other than just overt inflammation or damage involved in arthritis pain. In neuropathic pain disinhibition and microglial effects have been well-described. Recently, complement-mediated microglial synapse removal...

There is an imperfect correlation between joint changes and pain in arthritis, suggesting that there may be mechanisms other than just overt inflammation or damage involved in arthritis pain. In neuropathic pain disinhibition and microglial effects have been well-described. Here, we aim to demonstrate in models of arthritis that complement-mediated...

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying several physiological functions such as touch and pain sensing, hearing and proprioception. This process is carried out by specialized mechanosensitive ion channels whose identities have been discovered for most functions except pa...

Functional changes in hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels have been shown to contribute to medial prefrontal (mPFC) hyperexcitability after peripheral nerve injury. A reduction in the open probability of these neuronal channels might be relevant since this can enhance membrane input resistance and synaptic summati...

NTRODUCTION: Pain upon movement is a major complaint of arthritis patients and remains poorly managed. Unfortunately, as mechanisms of pain in arthritis are incompletely understood, it is difficult to develop novel efficacious therapies. The Complete Freund’s Adjuvant (CFA) intra-articular model of inflammatory arthritis is widely used and results...

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGF...

Chronic pain affects a third of the population and current treatments produce limited relief and severe side effects. An alternative strategy to decrease pain would be to directly modulate somatosensory pathways using optogenetics. Optogenetics involves the use of genetically encoded and optically active proteins, namely opsins, to control neuronal...

Primary C-fiber nociceptors are broadly divided into peptidergic and non-peptidergic afferents. TRPV1 is a thermosensitive cation channel mainly localized in peptidergic nociceptors whereas MrgD is a sensory G protein-coupled receptor expressed in most non-peptidergic nociceptive afferents. TRPV1 and MrgD fibers have been reported to be primarily i...

Les traitements actuels contre la douleur chronique procurent peu d’analgésie mais d’importants effets secondaires. Une alternative serait de moduler l’activité neuronale directement à l’aide de l’optogénétique, une thérapie génique impliquant l’utilisation de protéines photo-activables. Dans les modèles animaux, cette approche diminue les douleurs...

Significance Distinct cellular stresses converge on the translation initiation factor, eukaryotic initiation factor 2α (eIF2α) to modulate the rate of protein synthesis. Increased phosphorylation of eIF2α has been described in peripheral neurons from neuropathic and diabetic rats. However, the role of eIF2α phosphorylation in pain has not been repo...

Aim of Investigation Approximately 1 in 5 adults in developed countries have doctor-diagnosed arthritis. Pain is the most commonly reported symptom in these patients but pain treatments are often suboptimal. Improvements are needed in analgesic treatments; there is a particular need for those with a different mechanism of action from those of curre...

[This corrects the article DOI: 10.1038/celldisc.2016.17.].

Platelet-activating factor (PAF) is a pleiotropic phospholipid with proinflammatory, procoagulant and angiogenic actions on the vasculature. We and others have reported the presence of PAF receptor (Ptafr) at intracellular sites such as the nucleus. However, mechanisms of localization and physiologic functions of intracellular Ptafr remain poorly u...

We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8⁺ primary afferents using the Nav1.8-Cre driver line....

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is lo...

Supplementary Figures 1-8

The superficial dorsal horn represents the first location in the CNS where the modulation of pain-related information takes place before being forwarded to higher centers. Although it is assumed that changes in the circuitry and excitability of its neurons play a major role in the genesis of pain states, we still know too little about this region o...

Neuropathic pain is a chronic debilitating disease that results from nerve damage, persists long after the injury has subsided, and is characterized by spontaneous pain and mechanical hypersensitivity. Although loss of inhibitory tone in the dorsal horn of the spinal cord is a major contributor to neuropathic pain, the molecular and cellular mechan...

Background: Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervat...

Background Non-peptidergic nociceptive neurons are a sub-population of small diameter primary sensory neurons that comprise approximately 50 % of the C fiber population. Together with the peptidergic sub-population, they transmit nociceptive information from the periphery to the superficial dorsal horn of the spinal cord. Despite the numerous studi...

Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding...

Neuropeptide Y (NPY) has been implicated in the modulation of pain. Under normal conditions, NPY is found in interneurons in the dorsal horn of the spinal cord and in sympathetic postganglionic neurons but is absent from the cell bodies of sensory neurons. Following peripheral nerve injury NPY is dramatically upregulated in the sensory ganglia. How...

The traditional view of G protein-coupled receptors (GPCRs) being inactivated upon their internalization has been repeatedly challenged in recent years. GPCRs, in addition to forming the largest family of cell surface receptors, can also be found on intracellular membranes such as nuclear membranes. Since the first experimental evidence of GPCRs at...

Neurons have an important role in retinal vascular development. Here we show that the G protein-coupled receptor (GPCR) coagulation factor II receptor-like 1 (F2rl1, previously known as Par2) is abundant in retinal ganglion cells and is associated with new blood vessel formation during retinal development and in ischemic retinopathy. After stimulat...

Inhibitory interneurons are an important component of dorsal horn circuitry where they serve to modulate spinal nociception. There is now considerable evidence indicating that reduced inhibition in the spinal dorsal horn contributes to neuropathic pain. A loss of these inhibitory neurons after nerve injury is one of the mechanisms being proposed to...

Whereas both GABAA receptors (GABAARs) and glycine receptors (GlyRs) play a role in control of dorsal horn neuron excitability, their relative contribution to inhibition of small diameter primary afferent terminals remains controversial. To address this, we designed an approach for quantitative analyses of the distribution of GABAAR-subunits, GlyR...

To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications. Clinical study-In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were mea...

We report a novel model in which remote activation of peripheral nociceptive pathways in transgenic mice is achieved optogenetically, without any external noxious stimulus or injury. Taking advantage of a binary genetic approach, we selectively targeted Nav1.8(+) sensory neurons for conditional expression of channelrhodopsin-2 (ChR2) channels. Acut...

We have previously shown a sprouting of sympathetic fibers into the upper dermis of the skin following subcutaneous injection of complete Freund's adjuvant (CFA) into the hindpaw. This sprouting correlated with an increase in pain-related sensitivity. We hypothesized that this sprouting and pain-related behavior were caused by an increase in nerve...

Although chronic pain is the most common symptom of arthritis, relatively little is known about the mechanisms driving it. Recently, a sprouting of autonomic sympathetic fibers into the upper dermis of the skin, an area that is normally devoid of them, was found in the skin following chronic inflammation of the rat hindpaw. While this sprouting onl...

Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons which express...

Endogenous acetylcholine (ACh) is a well-known modulator of nociceptive transmission in the spinal cord of rodents. It arises mainly from a sparse population of cholinergic interneurons located in the dorsal horn of the spinal cord. This population was thought to be absent from the spinal cord of monkey, what might suggest that spinal ACh would not...

Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent evidence for co-expression of metabotropic P2Y receptors with P2X3 suggests that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with stro...

Background Pain-related (nociceptive) information is carried from the periphery to the dorsal horn of the spinal cord mostly by two populations of small diameter primary afferents, the peptidergic and the non-peptidergic. The peptidergic population expresses neuropeptides, such as substance P and calcitonin gene-related peptide, while the non-pepti...