Central projections of nociceptive input originating from the low back and limb muscle in rats.

Since clinical features of chronic muscle pain originating from the low back and limbs are different (higher prevalence and broader/duller sensation of low back muscle pain than limb muscle pain), spinal and/or supraspinal projection of nociceptive information could differ between the two muscles. We tested this hypothesis using c-Fos immunohistochemistry combined with retrograde-labeling of dorsal horn (DH) neurons projecting to ventrolateral periaqueductal grey (vlPAG) or ventral posterolateral nucleus of the thalamus (VPL) by fluorogold (FG) injections into the vlPAG or VPL. C-Fos expression in the DH was induced by injecting 5% formalin into the multifidus (MF, low back) or gastrocnemius-soleus (GS, limb) muscle.

Persistent muscle hyperalgesia after adolescent stress is exacerbated by a mild-nociceptive input in adulthood and is associated with microglia activation.

Non-specific low back pain (LBP) is a major global disease burden and childhood adversity predisposes to its development. The mechanisms are largely unknown. Here, we investigated if adversity in young rats augments mechanical hyperalgesia and how spinal cord microglia contribute to this.

TRPM3-mediated dynamic mitochondrial activity in nerve growth factor-induced latent sensitization of chronic low back pain.

The transient receptor potential ion channel TRPM3 is highly prevalent on nociceptive dorsal root ganglion (DRG) neurons, but its functions in neuronal plasticity of chronic pain remain obscure. In an animal model of nonspecific low back pain (LBP), latent spinal sensitization known as nociceptive priming is induced by nerve growth factor (NGF) injection. Here, we address the TRPM3-associated molecular basis of NGF-induced latent spinal sensitization at presynaptic level by studying TRPM3-mediated calcium transients in DRG neurons.

Rat dorsal horn neurons primed by stress develop a long-lasting manifest sensitization after a short-lasting nociceptive low back input.

Background: A single injection of nerve growth factor (NGF) into a low back muscle induces a latent sensitization of rat dorsal horn neurons (DHNs) that primes for a manifest sensitization by a subsequent second NGF injection. Repeated restraint stress also causes a latent DHN sensitization.

Objective: In this study, we investigated whether repeated restraint stress followed by a single NGF injection causes a manifest sensitization of DHNs.

Spinal cord fractalkine (CX3CL1) signaling is critical for neuronal sensitization in experimental nonspecific, myofascial low back pain.

Neuroactive substances released by activated microglia contribute to hyperexcitability of spinal dorsal horn neurons in many animal models of chronic pain. An important feedback loop mechanism is via release of fractalkine (CX3CL1) from primary afferent terminals and dorsal horn neurons and binding to CX3CR1 receptors on microglial cells. We studied the involvement of fractalkine signaling in latent and manifest spinal sensitization induced by two injections of nerve growth factor (NGF) into the lumbar multifidus muscle as a model for myofascial low back pain.

Action potentials and subthreshold potentials of dorsal horn neurons in a rat model of myositis: a study employing intracellular recordings in vivo.

Intracellular in vivo recordings from rat dorsal horn neurons were made to study the contribution of microglia to the central sensitization of spinal synapses induced by a chronic muscle inflammation. To block microglia activation, minocycline was continuously administered intrathecally during development of the inflammation. The aim was to test whether an inflammation-induced sensitization of dorsal horn neurons is mediated by changes in synaptic strength or other synaptic changes and how activated microglia influence these processes.

Prevention and reversal of latent sensitization of dorsal horn neurons by glial blockers in a model of low back pain in male rats.

In an animal model of nonspecific low back pain, recordings from dorsal horn neurons were made to investigate the influence of glial cells in the central sensitization process. To induce a latent sensitization of the neurons, nerve growth factor (NGF) was injected into the multifidus muscle; the manifest sensitization to a second NGF injection 5 days later was used as a read-out. The sensitization manifested in increased resting activity and in an increased proportion of neurons responding to stimulation of deep somatic tissues.

Evidence for the existence of nociceptors in rat thoracolumbar fascia.

Recently, the existence of nociceptive fibers in fascia tissue has attracted much interest. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, little is known about the properties of fascia nociceptors and possible changes of the fascia innervation by nociceptors under pathological circumstances.

Electrical high-frequency stimulation of the human thoracolumbar fascia evokes long-term potentiation-like pain amplification.

Nociceptive long-term potentiation, a use dependent increase in synaptic efficacy in the dorsal horn of the spinal cord is thought to contribute to the development of persistent pain states. So far, no study has analyzed the effects of high-frequency stimulation (HFS) of afferents from deep tissues (muscle and fascia) on pain perception in the back in humans. In 16 healthy volunteers, the multifidus muscle and the overlying thoracolumbar fascia were stimulated with electrical high-frequency pulses (5 × 100 pulses at 100 Hz) through bipolar concentric needle electrodes placed at lumbar level (L3/L4).

High-frequency modulation of rat spinal field potentials: effects of slowly conducting muscle vs. skin afferents.

Long-term potentiation (LTP) in rat spinal dorsal horn neurons was induced by electrical high-frequency stimulation (HFS) of afferent C fibers. LTP is generally assumed to be a key mechanism of spinal sensitization. To determine the contribution of skin and muscle afferents to LTP induction, the sural nerve (SU, pure skin nerve) or the gastrocnemius-soleus nerve (GS, pure muscle nerve) were stimulated individually.

Comparison of nerve growth factor-induced sensitization pattern in lumbar and tibial muscle and fascia.

Introduction: Nerve growth factor (NGF) induces profound hyperalgesia. In this study we explored patterns of NGF sensitization in muscle and fascia of distal and paraspinal sites.

Methods: We injected 1 µg of NGF into human (n = 8) tibialis anterior and erector spinae muscles and their fasciae.

Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain.

The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception.

Sensory findings after stimulation of the thoracolumbar fascia with hypertonic saline suggest its contribution to low back pain.

Injection of hypertonic saline into deep tissues of the back (subcutis, muscle, or the surrounding fascia) can induce acute low back pain (LBP). So far, no study has analyzed differences in temporal, qualitative, and spatial pain characteristics originating from these tissues. The current study aimed to investigate the role of the thoracolumbar fascia as a potential source of LBP.

Injection of nerve growth factor into a low back muscle induces long-lasting latent hypersensitivity in rat dorsal horn neurons.

Little is known about the central mechanisms underlying the transition from local or regional to widespread pain in low back pain patients. The aim of the study was to find out if muscle input induced by injection of nerve growth factor (NGF) can be used as an animal model for studying spinal mechanisms involved in widespread myofascial low back pain. Electrophysiological recordings from rat dorsal horn neurons were made in vivo to study alterations in their responsiveness caused by 2 injections of NGF into the multifidus muscle at an interval of 5 days.

Shock wave treatment improves nerve regeneration in the rat.

Introduction: The aims of the experiments were to: (1) determine whether low-energy shock wave treatment accelerates the recovery of muscle sensitivity and functionality after a nerve lesion; and (2) assess the effect of shock waves on the regeneration of injured nerve fibers.

Methods: After compression of a muscle nerve in rats the effects of shock wave treatment on the sequelae of the lesion were tested. In non-anesthetized animals, pressure pain thresholds and exploratory activity were determined.

Tetrodotoxin-resistant fibres and spinal Fos expression: differences between input from muscle and skin.

Nociceptive information from muscle and skin is differently processed at many levels of the central nervous system. In most articles on this issue, noxious stimuli were used that also excited non-nociceptive receptors. The effects of a pure nociceptive input from muscle or skin on spinal neurones are largely unknown.

Nociceptive input from the rat thoracolumbar fascia to lumbar dorsal horn neurones.

In anaesthetised rats, systematic electrophysiological recordings from dorsal horn neurones in spinal segments Th13-L5 were made to obtain information about the spinal nociceptive processing from the lumbar thoracolumbar fascia. Six to fourteen percent of the neurones in the spinal segments Th13-L2 had nociceptive input from the thoracolumbar fascia in naïve animals, no neurones responsive to input from the lumbar fascia were found in segments L3-L5. The segmental location of the receptive fields in the fascia was shifted 2-4 segments caudally relative to the spinal segment recorded from.

Role of spinal microglia in myositis-induced central sensitisation: an immunohistochemical and behavioural study in rats.

There is increasing evidence that spinal glial cells play an important role in chronic pain states. However, so far no data on the role of microglia in muscle pain are available. The aim of the present study was to investigate the involvement of spinal microglial cells in chronic muscle pain.

Dorsal horn neurons having input from low back structures in rats.

The mechanisms of nociception in the low back are poorly understood, partly because systematic recordings from dorsal horn neurons with input from the low back are largely missing. The purpose of this investigation was to (1) identify spinal segments and dorsal horn neurons receiving input from the low back, (2) test the effect of nerve growth factor (NGF) injected into the multifidus muscle (MF) on the neurons' responsiveness, and (3) study the influence of a chronic MF inflammation on the responses. In rats, microelectrode recordings were made in the segments L2, L3, and L5 to find dorsal horn neurons having input from the low back (LB neurons).

Neuroanatomical pathway of nociception originating in a low back muscle (multifidus) in the rat.

The neural mechanisms of low back pain (LBP) are still enigmatic. Presently, low back muscles are being discussed as an important source of LBP. Here, the neuroanatomical pathway of the nociceptive information from the caudal multifidus muscle (MF) was studied.

Sensitization of rat dorsal horn neurons by NGF-induced subthreshold potentials and low-frequency activation. A study employing intracellular recordings in vivo.

Intramuscular injection of NGF in human subjects has been reported not to elicit pain, whereas 5% NaCl does. On the other hand, NGF injections induce a long-lasting hyperalgesia. In the present study, the possible neuronal basis of these effects was studied at the spinal level.

Effects on c-Fos expression in the PAG and thalamus by selective input via tetrodotoxin-resistant afferent fibres from muscle and skin.

Nociceptive information from skin and muscle is differently processed at many levels of the central nervous system. However, with regard to nociceptive input from muscle to the thalamus, only few data are available. Here, we investigated the c-Fos expression in the thalamus and the periaqueductal grey matter (PAG) induced by electrical stimulation of tetrodotoxin-resistant (TTX-r), presumably nociceptive, afferent fibres.

The possible role of the NO-cGMP pathway in nociception: different spinal and supraspinal action of enzyme blockers on rat dorsal horn neurones.

In the literature, the pro- or antinociceptive effects of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are discussed controversially. Our laboratory and others have reported that in the spinal cord a local lack of NO has an excitatory action on the ongoing (background) activity of dorsal horn neurones. Here, we tested the hypothesis that this effect of NO is mediated by cGMP and that part of the controversy is due to differences in the spinal and supraspinal actions of both compounds.

Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat.

In inflamed tissue--including skeletal muscle--the concentrations of cytokines and neurotrophins are known to increase. However, nothing is known about a possible contribution of these agents to muscle pain and hyperalgesia. The present study investigated acute effects of cytokines and neurotrophins on response properties of slowly conducting muscle afferents.