Intraoperative Spinal Cord Stimulation Mitigates Central Sensitization After Spine Surgery in Mice.

Study Design: Double-blinded, prospective laboratory animal study.

Objective: To examine whether intraoperative spinal cord stimulation (SCS) inhibits the development of spine surgery-induced hypersensitivity.

Summary Of Background Data: Managing postoperative pain after spine surgery is challenging, and as many as 40% of patients may develop failed back surgery syndrome.

Spinal GABAergic disinhibition allows microglial activation mediating the development of nociplastic pain in male mice.

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury.

Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling.

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression.

Gonadal hormone-dependent nociceptor sensitization maintains nociplastic pain state in female mice.

Nociplastic pain conditions develop predominantly in women. We recently established a murine nociplastic pain model by applying postinjury thermal (40°C) stimulation to an injured (capsaicin-injected) area, triggering a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. The nociplastic pain state was centrally maintained by spinal microglia in males but peripherally by ongoing afferent activity at the previously injured area in females.

A neuron-to-astrocyte Wnt5a signal governs astrogliosis during HIV-associated pain pathogenesis.

Chronic pain is the most common neurological disorder of HIV patients. Multiple neuropathologies were identified in the pain pathway. Among them is the prominent astrocytic reaction (also know an astrogliosis).

Neuron Type-Dependent Synaptic Activity in the Spinal Dorsal Horn of Opioid-Induced Hyperalgesia Mouse Model.

Opioids are widely used for pain relief; however, chronic opioid use causes a paradoxical state of enhanced pain sensitivity, termed "Opioid-induced hyperalgesia (OIH)." Despite the clinical importance of OIH, the detailed mechanism by which it enhances pain sensitivity remains unclear. In this study, we tested whether repeated morphine induces a neuronal circuit polarization in the mouse spinal dorsal horn (SDH).

Postinjury stimulation triggers a transition to nociplastic pain in mice.

Acute injury-induced pain can transition to chronic nociplastic pain, which predominantly affects women. To facilitate studies on the underlying mechanisms of nociplastic pain, we developed a mouse model in which postinjury thermal stimulation (intermittent 40°C water immersion for 10 minutes at 2 hours postcapsaicin) prolongs capsaicin (ie, experimental injury)-induced transient mechanical hypersensitivity outside of the injury area. Although capsaicin injection alone induced mechanical and thermal hypersensitivity that resolved in ∼7 days (slower recovery in females), the postinjury stimulation prolonged capsaicin-induced mechanical, but not thermal, hypersensitivity up to 3 weeks in both sexes.

HIV-related Neuropathy: Pathophysiology, Treatment and Challenges.

HIV-sensory neuropathy (HIV-SN) is a debilitating complication in HIV patients with or without anti-retroviral treatment (ART). Common symptoms of HIV-SN include pain, decreased sensation, paresthesias, and dysesthesias in a symmetric stocking-glove distribution. While HIV-1 protein such as gp120 is implicated in HIV-SN (e.

Low-intensity, Kilohertz Frequency Spinal Cord Stimulation Differently Affects Excitatory and Inhibitory Neurons in the Rodent Superficial Dorsal Horn.

Since 1967, spinal cord stimulation (SCS) has been used to manage chronic intractable pain of the trunk and limbs. Compared to traditional high-intensity, low-frequency (<100 Hz) SCS that is thought to produce paresthesia and pain relief by stimulating large myelinated fibers in the dorsal column (DC), low-intensity, high-frequency (10 kHz) SCS has demonstrated long-term pain relief without generation of paresthesia. To understand this paresthesia-free analgesic mechanism of 10 kHz SCS, we examined whether 10 kHz SCS at intensities below sensory thresholds would modulate spinal dorsal horn (DH) neuronal function in a neuron type-dependent manner.

Maternal vaccination and protective immunity against Zika virus vertical transmission.

An important goal of the Zika virus (ZIKV) vaccine is to prevent a congenital syndrome in fetuses of pregnant women, but studies directly evaluating maternal vaccination for ZIKV are lacking. Here we report maternal vaccination using a live-attenuated ZIKV vaccine (3'UTR-∆10-LAV) in a pregnant mouse model. Maternal immunization with 3'UTR-∆10-LAV does not cause any adverse effects on pregnancy, fetal development, or offspring behavior.

The Relationship Between β-Endorphin and Experimental Pain Sensitivity in Older Adults With Knee Osteoarthritis.

Osteoarthritis (OA) is the most common cause of pain in people aged 45 years, and the knee is the most commonly affected joint. There is a growing interest in understanding the biological factors that influence pain among older adults, but few studies have examined the relationship between β-endorphin and experimental pain sensitivity in older adults with knee OA pain. The purpose of this study was to investigate the relationship between resting plasma levels of β-endorphin and experimental pain sensitivity.

Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse side effect of many anti-cancer chemotherapeutic treatments. CIPN often causes neuropathic pain in extremities, and oxidative stress has been shown to be a major contributing factor to this pain. In this study, we determined the site of oxidative stress associated with pain (specifically, mechanical hypersensitivity) in cisplatin- and paclitaxel-treated mouse models of CIPN and investigated the neurophysiological mechanisms accounting for the pain.

Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice.

Reactive oxygen species has been suggested as a key player in neuropathic pain, causing central sensitization by changing synaptic strengths in spinal dorsal horn neurons. However, it remains unclear as to what type of reactive oxygen species changes what aspect of synaptic strengths for central sensitization in neuropathic pain conditions. In this study, we investigated whether mitochondrial superoxide affects both excitatory and inhibitory synaptic strengths in spinal dorsal horn neurons after peripheral nerve injury.

An Energy-Efficient Wirelessly Powered Millimeter-Scale Neurostimulator Implant Based on Systematic Codesign of an Inductive Loop Antenna and a Custom Rectifier.

In this work, a switched-capacitor-based stimulator circuit that enables efficient energy harvesting for neurostimulation applications is presented, followed by the discussion on the optimization of the inductive coupling front-end through a codesign approach. The stimulator salvages input energy and stores it in a storage capacitor, and, when the voltage reaches a threshold, releases the energy as an output stimulus. The dynamics of the circuit are automatically enabled by a positive feedback, eliminating any stimulation control circuit blocks.

Acupuncture points can be identified as cutaneous neurogenic inflammatory spots.

Acupuncture, a traditional medical procedure practised for over 2000 years in Asia, stimulates specific but poorly defined sites called acupoints. To date, no unique anatomical acupoint structures have been found. However, noxious sensory signals from visceral organs produce hypersensitive spots on the skin (neurogenic spots), caused by cutaneous neurogenic inflammation, in the dermatome that overlaps with visceral afferent innervations.

Reactive oxygen species affect spinal cell type-specific synaptic plasticity in a model of neuropathic pain.

Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) and in LTD in GABAn (GABAn-LTD).

Differential involvement of reactive oxygen species in a mouse model of capsaicin-induced secondary mechanical hyperalgesia and allodynia.

Intradermally injected capsaicin induces secondary mechanical hyperalgesia and allodynia outside the primary (i.e., capsaicininjected) site.

Dysregulation of Norepinephrine Release in the Absence of Functional Synaptotagmin 7.

Synaptotagmin 7 (Syt7) is expressed in cardiac sympathetic nerve terminals where norepinephrine (NE) is released in both Ca(2+)-dependent exocytosis and Ca(2+)-independent norepinephrine transporter (NET)-mediated overflow. The role of Syt7 in the regulation of NE release from cardiac sympathetic nerve terminals is tested by employing a Syt7 knock-in mouse line that expresses a non-functional mutant form of Syt7. In cardiac sympathetic nerve terminals prepared from these Syt7 knock-in mice, the Ca(2+)-dependent component of NE release was diminished.

Induction of long-term potentiation and long-term depression is cell-type specific in the spinal cord.

The underlying mechanism of chronic pain is believed to be changes in excitability in spinal dorsal horn (DH) neurons that respond abnormally to peripheral input. Increased excitability in pain transmission neurons, and depression of inhibitory neurons, are widely recognized in the spinal cord of animal models of chronic pain. The possible occurrence of 2 parallel but opposing forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) was tested in 2 types of identified DH neurons using whole-cell patch-clamp recordings in mouse spinal cord slices.

Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse.

One feature of neuropathic pain is a reduced spinal gamma-aminobutyric acid (GABA)-ergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice.

Reactive oxygen species (ROS) modulate AMPA receptor phosphorylation and cell-surface localization in concert with pain-related behavior.

Sensitization of dorsal horn neurons (DHNs) in the spinal cord is dependent on pain-related synaptic plasticity and causes persistent pain. The DHN sensitization is mediated by a signal transduction pathway initiated by the activation of N-methyl-d-aspartate receptors (NMDA-Rs). Recent studies have shown that elevated levels of reactive oxygen species (ROS) and phosphorylation-dependent trafficking of GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) are a part of the signaling pathway for DHN sensitization.

Regulation of Wnt signaling by nociceptive input in animal models.

Background: Central sensitization-associated synaptic plasticity in the spinal cord dorsal horn (SCDH) critically contributes to the development of chronic pain, but understanding of the underlying molecular pathways is still incomplete. Emerging evidence suggests that Wnt signaling plays a crucial role in regulation of synaptic plasticity. Little is known about the potential function of the Wnt signaling cascades in chronic pain development.

Mitochondrial Ca(2+) uptake is essential for synaptic plasticity in pain.

The increase of cytosolic free Ca(2+) ([Ca(2+)](c)) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that [Ca(2+)](c) does not trigger synaptic plasticity directly but must first enter into mitochondria.