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Scientific Reports Oct 2021This study aims to evaluate the relation between the lumbosacral trunk (LT) and the sacro-iliac joint (SIJ). In forty anatomic specimens (hemipelves) a classical...
This study aims to evaluate the relation between the lumbosacral trunk (LT) and the sacro-iliac joint (SIJ). In forty anatomic specimens (hemipelves) a classical antero-lateral approach to the SIJ was performed. The SIJ was marked at the linea terminalis (reference point A). Reference point B was situated at the upper edge of the interosseous sacro-iliac ligament. The length of the SIJ (distance A to B) and the distance between point A and the ventral branch of the fourth (L4) and fifth (L5) lumbar spinal nerves at the linea terminalis were measured. The SIJ had a mean length of 58.0 mm. The ventral branch of L5 was located closer to the SIJ in very long SIJs (mean length: ≥ 6.5 cm; mean distance: 9.8 mm) compared to very short joints (≤ 5 mm; mean distance: 11.3 mm). For the ventral branch of L4, very long SIJs had a mean distance of 7 mm and very short joints an average distance of 9.7 mm between point A and the nerve branch. A safe zone of approximately 1 cm to 2 cm (anterior to posterior) is present on the sacral surface (lateral to medial) for safe fixation of plates during anterior plate stabilization of the SIJ. Pelves with a shorter dorsoventral diameter of the most superior part of the SIJ apparently give more space for inserting plates.
Topics: Aged; Aged, 80 and over; Bone Plates; Cadaver; Female; Humans; Lumbosacral Plexus; Male; Middle Aged; Sacroiliac Joint; Spinal Nerves
PubMed: 34642441
DOI: 10.1038/s41598-021-99851-3 -
Brain Research Sep 2010The balance between descending inhibition and facilitation is thought to be disturbed in chronic pain states. Increased facilitation by spinally released serotonin has...
The balance between descending inhibition and facilitation is thought to be disturbed in chronic pain states. Increased facilitation by spinally released serotonin has been suggested by demonstration that mechanically evoked neuronal responses of wide dynamic range neurons are inhibited by 5-HT3 receptor antagonists in rats following spinal nerve ligation (SNL) but not sham operation. Despite these physiologic data, the effects of spinal 5-HT3 receptor blockade on behavioral hypersensitivity and neurochemical alterations in spinal serotonergic system have not been thoroughly investigated following spinal nerve ligation in the rat. To test this, we acutely injected intrathecal ondansetron in rats between 14 and 30 days after SNL and assessed effects on thermal and mechanical hypersensitivity. We also determined the density of serotonergic nerve fibers, serotonin content and the levels of 5-HT3 receptors within the spinal cord at this time point. Intrathecal ondansetron (1, 3, 10, 30, and 100microg) produced no effect on behavioral measures of thermal or mechanical hypersensitivity whereas intrathecal morphine (1microg) and gabapentin (200microg) partially reversed thermal and mechanical hypersensitivity following SNL. In addition, SNL did not alter the density of serotonergic fibers or 5-HT3 receptor immunoreactivity or spinal tissue content of 5-HT within the dorsal horn. These results do not support anatomic plasticity of descending serotonergic pathways or tonic 5-HT3 receptor activity in maintaining hypersensitivity after nerve injury and in contrast to previous studies fail to demonstrate an anti-hypersensitivity effect of intrathecal injection of the 5-HT3 receptor antagonist ondansetron. Importantly, behavioral measures of mechanical hypersensitivity assess threshold responses whereas physiological studies of mechanically evoked neuronal responses involve application of suprathreshold stimuli. Thus, suprathreshold or more intense stimuli may be necessary to recruit descending serotonergic facilitatory drive required to observe the inhibitory effects of ondansetron on spinal neuronal excitability and behavioral hypersensitivity.
Topics: Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Excitatory Amino Acid Antagonists; Gabapentin; Indoles; Injections, Spinal; Ligation; Ondansetron; Pain; Quinolizines; Rats; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Spinal Nerves; gamma-Aminobutyric Acid
PubMed: 20637741
DOI: 10.1016/j.brainres.2010.07.020 -
Pain Jun 2008Many treatments for neuropathic pain activate or augment norepinephrine release in the spinal cord, yet these treatments are less effective against acute nociceptive...
Many treatments for neuropathic pain activate or augment norepinephrine release in the spinal cord, yet these treatments are less effective against acute nociceptive stimuli. We previously showed in mice that peripheral nerve injury results in sprouting of spinal noradrenergic fibers, possibly reflecting the substrate for this shift in drug efficacy. Here, we tested whether such sprouting also occurs in rats after nerve injury and examined one signal for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in hypersensitivity to tactile stimulation of the ipsilateral paw, and sprouting of noradrenergic fibers in the dorsal horn of the lumbar spinal cord. Brain derived nerve growth factor (BDNF) content increased in L4-L6 dorsal root ganglia ipsilateral to injury and in lumbar spinal cord following nerve injury, and intrathecal infusion of BDNF antiserum prevented spinal noradrenergic sprouting. This treatment also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. Intraspinal injection of BDNF in non-injured rats mimicked the sprouting of spinal noradrenergic fibers seen after nerve injury. These results suggest that increased BDNF synthesis and release drives spinal noradrenergic sprouting following nerve injury, and that this sprouting may paradoxically increase the capacity for analgesia in the setting of neuropathic pain from drugs which utilize or mimic the noradrenergic pathway.
Topics: Analgesics; Animals; Brain-Derived Neurotrophic Factor; Clonidine; Drug Combinations; Drug Synergism; Male; Nerve Fibers; Neuralgia; Norepinephrine; Rats; Rats, Sprague-Dawley; Spinal Nerves
PubMed: 17822849
DOI: 10.1016/j.pain.2007.07.014 -
ELife May 2020Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of...
Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.
Topics: Animals; Astrocytes; Axon Guidance; Cell Line; Chick Embryo; Chickens; Developmental Biology; Gene Knockdown Techniques; Growth Cones; Humans; Membrane Proteins; Neurosciences; Nitric Oxide; Procollagen-Proline Dioxygenase; Protein Disulfide-Isomerases; Rats; Signal Transduction; Somites; Spinal Nerves
PubMed: 32452761
DOI: 10.7554/eLife.54612 -
Pain Research & Management 2019Neuropathic pain remains underrecognised and ineffectively treated in chronic pain sufferers. Consequently, their quality of life is considerably reduced, and...
Neuropathic pain remains underrecognised and ineffectively treated in chronic pain sufferers. Consequently, their quality of life is considerably reduced, and substantial healthcare costs are incurred. The anatomical location of pain must be identified for definitive diagnosis, but current neuropsychological tools cannot do so. Matrix metalloproteinases (MMP) are thought to maintain peripheral neuroinflammation, and MMP-12 is elevated particularly in such pathological conditions. Magnetic resonance imaging (MRI) of the peripheral nervous system has made headway, owing to its high-contrast resolution and multiplanar features. We sought to improve MRI specificity of neural lesions, by constructing an MMP-12-targeted magnetic iron oxide nanoparticle (IONP). Its efficiency was evaluated in a rodent model of neuropathic pain, where the left lumbar 5 (L5) spinal nerve was tightly ligated. Spinal nerve ligation (SNL) successfully induced mechanical allodynia, and thermal hyperalgesia, in the left hind paw throughout the study duration. These neuropathy characteristics were absent in animals that underwent sham surgery. MMP-12 upregulation with concomitant macrophage infiltration, demyelination, and elastin fibre loss was observed at the site of ligation. This was not observed in spinal nerves contralateral and ipsilateral to the ligated spinal nerve or uninjured left L5 spinal nerves. The synthesised MMP-12-targeted magnetic IONP was stable and nontoxic . It was administered onto the left L5 spinal nerve by intrathecal injection, and decreased magnetic resonance (MR) signal was observed at the site of ligation. Histology analysis confirmed the presence of iron in ligated spinal nerves, whereas iron was not detected in uninjured left L5 spinal nerves. Therefore, MMP-12 is a potential biomarker of neuropathic pain. Its detection , using IONP-enhanced MRI, may be further developed as a tool for neuropathic pain diagnosis and management.
Topics: Animals; Disease Models, Animal; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Matrix Metalloproteinase 12; Neuralgia; Rats, Sprague-Dawley; Spinal Nerves
PubMed: 30956741
DOI: 10.1155/2019/9394715 -
Pain Apr 2020Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of...
Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ heteromer expression in L5 DRG but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, subcutaneously). HEK-293T cell surface-labeled with µ- and δ-ORs internalized both receptors after exposure to CYM51010. By contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-δ heterodimerization in uninjured DRG neurons, and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.
Topics: Animals; Ganglia, Spinal; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Neuralgia; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Rodentia; Spinal Nerves
PubMed: 31815916
DOI: 10.1097/j.pain.0000000000001768 -
European Journal of Pain (London,... Aug 2011Despite using prescribed pain medications, patients with neuropathic pain continue to experience moderate to severe pain. There is a growing recognition of a potent...
Despite using prescribed pain medications, patients with neuropathic pain continue to experience moderate to severe pain. There is a growing recognition of a potent peripheral opioid analgesia in models of inflammatory and neuropathic pain. The goal of this study was to characterize the temporal and spatial expression of mu opioid receptor (mOR) mRNA and protein in primary afferent neurons in a rat L5 spinal nerve ligation model of persistent neuropathic pain. Bilateral L4 and L5 dorsal root ganglia (DRGs), L4 and L5 spinal cord segments, and hind paw plantar skins were collected on days 0 (naïve), 3, 7, 14, and 35 post-spinal nerve ligation or post-sham surgery. We found that expression of mOR mRNA and protein in primary afferent neurons changed dynamically and site-specifically following L5 spinal nerve ligation. Real-time RT-PCR, immunohistochemistry, and Western blot analysis demonstrated a down-regulation of mOR mRNA and protein in the injured L5 DRG. In contrast, in the uninjured L4 DRG, mOR mRNA transiently decreased on day 7 and then increased significantly on day 14. Western blot analysis revealed a persistent increase in mOR protein expression, although immunohistochemistry showed no change in number of mOR-positive neurons in the uninjured L4 DRG. Interestingly, mOR protein expression was reduced in the skin on days 14 and 35 post-nerve injury and in the L4 and L5 spinal cord on day 35 post-nerve injury. These temporal and anatomically specific changes in mOR expression following nerve injury are likely to have functional consequences on pain-associated behaviors and opioid analgesia.
Topics: Animals; HEK293 Cells; Humans; Male; Neuralgia; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Spinal Cord; Spinal Nerves
PubMed: 21310637
DOI: 10.1016/j.ejpain.2010.11.018 -
Journal of Cellular and Molecular... Feb 2019Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many...
Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c-Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain.
Topics: Animals; Autophagosomes; Autophagy; Behavior, Animal; Hypoglycemic Agents; Ligation; Male; Metformin; Neuralgia; Rats; Rats, Sprague-Dawley; Spinal Nerves; Surgical Procedures, Operative
PubMed: 30451370
DOI: 10.1111/jcmm.14033 -
The Journal of Pain Jan 2011Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic...
A tropomyosine receptor kinase inhibitor blocks spinal neuroplasticity essential for the anti-hypersensitivity effects of gabapentin and clonidine in rats with peripheral nerve injury.
UNLABELLED
Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic systems, which are engaged or targeted by commonly used treatments for neuropathic pain. Since BDNF signals via tropomyosine receptor kinases (trks), we tested whether trk blockade by repeated spinal injection of the trk inhibitor K252a would reduce anatomical (spinal noradrenergic and cholinergic fiber density), functional (α2-adrenoceptor-mediated direct stimulation of spinal cholinergic terminals), and behavioral (anti-hypersensitivity from systemic gabapentin and spinal clonidine) plasticity, which depends on BDNF. Spinal K252a treatment did not alter hypersensitivity from spinal nerve ligation (SNL), but blocked the SNL-associated increase in dopamine-β-hydroxylase (DβH) fiber density in the spinal cord dorsal horn while reducing spinal choline acetyltransferase (ChAT)-immunoreactivity. K252a treatment also abolished the facilitatory effect of dexmedetomidine on KCl-evoked acetylcholine release in spinal cord synaptosomes and reduced the anti-hypersensitivity effects of oral gabapentin and spinal clonidine. These results suggest that spinal trk signaling is essential for the anatomic and functional plasticity in noradrenergic and cholinergic systems after nerve injury and consequently for the analgesia from drugs that rely on these systems.
PERSPECTIVE
Many drugs approved for neuropathic pain engage spinal noradrenergic and cholinergic systems for analgesia. This study demonstrates that spinal trk signaling after nerve injury is important to neuroplasticity of these systems, which is critical for the analgesic action of common treatments for neuropathic pain.
Topics: Acetylcholine; Amines; Analgesics; Animals; Carbazoles; Choline O-Acetyltransferase; Clonidine; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dopamine beta-Hydroxylase; Enzyme Inhibitors; Gabapentin; Indole Alkaloids; Male; Neuralgia; Neuronal Plasticity; Pain Measurement; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Spinal Nerves; Synaptosomes; Time Factors; gamma-Aminobutyric Acid
PubMed: 20638911
DOI: 10.1016/j.jpain.2010.05.005 -
Pain Aug 2020Previous studies have shown that the peripheral nerve regeneration process is linked to pain in several neuropathic pain models. Other studies show that sympathetic...
Previous studies have shown that the peripheral nerve regeneration process is linked to pain in several neuropathic pain models. Other studies show that sympathetic blockade may relieve pain in some pain models and clinical conditions. This study examined reduction in peripheral nerve regeneration as one possible mechanism for relief of neuropathic pain by sympathetic blockade. A "microsympathectomy," consisting of cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, reduced mechanical hypersensitivity in 2 different rat neuropathic pain models. In the spinal nerve ligation model, in which some functional regeneration and reinnervation of the ligated spinal nerve can be observed, microsympathectomy reduced functional and anatomical measures of regeneration as well as expression of growth-associated protein 43 (GAP43), a regeneration-related protein. In the spared nerve injury model, in which functional reinnervation is not possible and the futile regeneration process results in formation of a neuroma, microsympathectomy reduced neuroma formation and GAP43 expression. In both models, microsympathectomy reduced macrophage density in the sensory ganglia and peripheral nerve. This corroborates previous work showing that sympathetic nerves may locally affect immune function. The results further highlight the challenge of improving pain in neuropathic conditions without inhibiting peripheral nerve regeneration that might otherwise be possible and desired.
Topics: Animals; Disease Models, Animal; Female; Ganglia, Spinal; Male; Nerve Regeneration; Neuralgia; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Spinal Nerves; Sympathectomy
PubMed: 32701850
DOI: 10.1097/j.pain.0000000000001887