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This study was aimed at evaluating the efficacy of glucosamine and potential mechanisms of actions in a neuropathic pain model in rats.
Glucosamine (500, 1000 and 2000 mg/kg) was administered via gavage route, 1 day before the chronic constriction injury (CCI) of sciatic nerve and daily for 14 days (prophylactic regimen), or from days 5 to 14 post-injury (therapeutic regimen), as the indicators of neuropathic pain, mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed on days 0, 3, 5, 7, 10 and 14 after ligation. Inducible nitric oxide synthase (iNOS) and tumour necrosis factor alpha (TNF-α) gene expressions were measured by real-time polymerase chain reaction. TNF-α protein content was measured using the enzyme-linked immunosorbent assay method.
Three days after nerve injury, the threshold of pain was declined among animals subjected to neuropathic pain. Mechanical and cold allodynia, as well as thermal hyperalgesia were attenuated by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. However, existing pain was not decreased by this drug. Increased mRNA expression of iNOS and TNF-α was significantly reduced in the spinal cord of CCI animals by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. The overall expression of spinal TNF-α was increased by CCI, but this increase was reduced in animals receiving glucosamine prophylactic treatment.
Findings suggest that glucosamine as a safe supplement may be a useful candidate in preventing neuropathic pain following nerve injury. Antioxidant and anti-inflammatory effects may be at least in part responsible for the antinociceptive effects of this drug.
The present study aims to investigate the efficacy of intravenously injected mesenchymal stem cells (MSCs) in treating neuropathic pain either before or after its induction by a chronic constriction injury (CCI) model. Rats were divided into four groups: control group, neuropathic group, and treated groups (pre and postinduction) with i.v. mononuclear cells (106 cell/mL). For these rats, experimental testing for both thermal and mechanical hyperalgesia was evaluated. The cerebral cortex of the rats was dissected, and immunohistochemical analysis using anti-proliferating cell nuclear antigen (PCNA), CD117, nestin, and glial fibrillary acidic protein was performed. Our results showed that a single injection of MSCs (either preemptive/or post-CCI) produced equipotent effects on allodynia, mechanical hyperalgesia, and thermal response. Immunohistochemical analysis showed that the stem cells have reached the cerebral cortex. The injected group with MSCs before CCI showing few stem cells expressed PCNA, CD117, and nestin in the cerebral cortex. The group injected with MSCs after CCI, showing numerous recently proliferated CD117-, nestin-, PCNA-positive stem cells in the cerebral cortex. In conclusion, our findings demonstrate that the most probable effect of i.v. stem cells is the central anti-inflammatory effect, which opens concerns about how stem cells circulating in systemic administration to reach the site of injury.
Endogenous cannabinoids assist in regulation of hunger, pain perception, inflammation, and stress responses. Tetrahydrocannabinol (THC), a component of cannabis, activates cannabinoid receptors, producing effects that are often emotionally pleasing and cognitively interesting. THC effects impair complex tasks, such as driving. Addiction develops in 8--10 percent of all cannabis users, and in about 25 percent of daily users. Regular adolescent users are especially vulnerable. Adverse outcomes of cannabis addiction include too much time spent intoxicated, important activities given up, worsening of psychological problems, and failed attempts to stop use. The withdrawal syndrome includes irritability, anxiety, depression, and sleep difficulties. Long-term heavy use of cannabis is associated with academic failure and subtle cognitive impairment. Medical uses of cannabis include relief of nausea, appetite improvement, and lessened neuropathic pain. Medical use may increase cannabis addiction, a risk somewhat similar to that of other, more traditional medications for pain, anxiety, and attention disorders. Because cannabis is now a commercial product, its potency has increased in recent years.
This is a case-control study to investigate the prevalence, characteristics, and risk factors of pain in patients with Parkinson's disease (PD).
A total of 200 PD patients from eastern China were enrolled in our study. Accordingly, 200 healthy elderly adults were recruited as controls. The characteristics of pain were collected by using the Visual Analog Scale, Brief Pain Inventory (BPI), SF-36 Bodily Pain Scale, Unified Parkinson's Disease Rating Scale, Hoehn–Yahr Scale (H-Y), Hamilton Depression Scale, and Leeds Assessment of Neuropathic Symptoms and Signs.
Of the 200 PD patients, pain was complained by 106 patients (53%). According to the SF-36 Bodily Pain Scale, pain morbidity in PD patients was significantly higher than in the control group. The average pain during last 24 h measured by the BPI was 2.67. About 76% of PD patients were found to have one pain type, 21.7% were having two pain types, and 1.9% had three pain types. Further, 69.8% of these patients were presented with musculoskeletal pain, 4.7% with dystonic pain, 22.6% with radicular-neuropathic pain, 20.8% with central neuropathic pain, and 9.4% with akathisia pain. The onset age and depression were the most significant predictors of pain in PD patients (p < 0.05). However, there was no significant association between pain and gender, age, disease duration, or severity of the disease. Only 5.7% of PD patients with pain received treatment in this study.
Pain is frequent and disabling, independent of demographic and clinical variables, and is significantly more common in PD patients.
Background: Chronic motor cortex stimulation (MCS) has been used to treat medically refractory neuropathic pain over the past 20 years. We investigated this procedure using a prospective multicentre randomized blinded crossover trial. Methods: Twelve subjects with three different neuropathic pain syndromes had placement of MCS systems after which they were randomized to receive low (“subtherapeutic”) or high (“therapeutic”) stimulation for 12 weeks, followed by a crossover to the other treatment group for 12 weeks. The primary outcome measure was the pain visual analogue scale (VAS). Secondary outcome measures included McGill Pain Questionnaire (MPQ), Beck Depression Inventory-II, medication log, work status, global impression of change, and SF-36 quality of life scale. Results: The trial was halted early due to lack of efficacy. One subject withdrew early due to protocol violation and five subjects withdrew early due to transient adverse events. Six subjects with upper extremity pain completed the study. There was no significant change in VAS with low or high stimulation and no significant improvement in any of the outcome measures from low to high stimulation. SF-36 role physical and mental health scores were worse with high compared to low stimulation (p=0.024, p=0.005). Conclusions: We failed to show that MCS is an effective treatment for refractory upper extremity neuropathic pain and suggest that previous studies may have been skewed by placebo effects, or ours by nocebo. We suggest that a healthy degree of skepticism is warranted when considering this invasive therapy for upper extremity pain syndromes.
To systematically summarise the peer-reviewed literature relating to the aetiology, clinical presentation, investigation and treatment of geniculate neuralgia.
Articles published in English between 1932 and 2012, identified using Medline, Embase and Cochrane databases.
The search terms ‘geniculate neuralgia’, ‘nervus intermedius neuralgia’, ‘facial pain’, ‘otalgia’ and ‘neuralgia’ were used to identify relevant papers.
Fewer than 150 reported cases were published in English between 1932 and 2012. The aetiology of the condition remains unknown, and clinical presentation varies. Non-neuralgic causes of otalgia should always be excluded by a thorough clinical examination, audiological assessment and radiological investigations before making a diagnosis of geniculate neuralgia. Conservative medical treatment is always the first-line therapy. Surgical treatment should be offered if medical treatment fails. The two commonest surgical options are transection of the nervus intermedius, and microvascular decompression of the nerve at the nerve root entry zone of the brainstem. However, extracranial intratemporal division of the cutaneous branches of the facial nerve may offer a safer and similarly effective treatment.
The response to medical treatment for this condition varies between individuals. The long-term outcomes of surgery remain unknown because of limited data.
This chapter focuses on the voltage-gated sodium (Nav) channel and voltage-gated calcium channel (VGCC), since they are essential to pain transmission. The most basic structural plan of a eukaryotic voltage-gated ion channel consists of four sub-units surrounding a central pore, through which ions pass. Sodium channel inactivation is modulated by many factors, including toxins, disease states, mutations, and therapeutic drugs. In neurons, activation of VGCC in response to depolarized membrane potential leads to calcium entry, mediating calcium-dependent enzyme activation, gene expression, or release of neurotransmitters. Two main classes of VGCC have been reported, the T-type or low voltage activated (LVA) and the high voltage activated (HVA) channels. To manage different etiologies of neuropathic pain, a variety of therapeutic targets must be available. Drugs directed at specific targets, such as those channels expressed in nociceptors, or upregulated after injury, may give the best pain management while minimizing undesirable side effects.
Multiple sclerosis (MS) can lead to numerous types of pain through the processes of inflammation and degeneration. The common types of pain seen in MS include dysesthetic/extremity pain, trigeminal neuralgia (TN), spasticity, L'hermitte's phenomenon, painful tonic spasms (PTS), musculoskeletal, headache, optic neuritis, and treatment related pain. This chapter focuses on the first five, with a particular focus on dysesthetic pain. The acute onset of dysesthetic pain in the setting of a relapse in a relapsing-remitting MS (RRMS) patient is clearly due to an inflammatory lesion. The inciting pathology of TN in MS is a lesion which affects the primary afferents of the trigeminal nerve after they enter the pons, distal to the trigeminal nuclear complex, in the root entry zone (REZ). Considering that people with MS are already predisposed to poor sleep, depression, and a poor quality of life, the presence of pain is particularly debilitating.
This chapter presents a detailed evidence of the involvement of algesic inflammatory mediators as well as anti-inflammatory mediators in neuropathic pain, including their structure, source, molecular targets, and effect on nociceptors, glia, and immune cells. It discusses some of the key inflammatory mediators implicated in neuropathic pain including kinins, purines, lipids, amines, and neurotrophic factors. Bradykinin contributes to ongoing inflammatory cascades by stimulating the release of pro-inflammatory cytokines and chemokines, as well as stimulating histamine release from mast cells. Cytokines, chemokines, and their receptors are widely expressed in the nervous system, and there is growing evidence they play a major role in the pathogenesis of neuropathic pain. Modulation of cytokine signaling by blocking pro-inflammatory cytokines and/or augmenting anti-inflammatory cytokines has shown considerable efficacy in models of neuropathy. Finally, the chapter discusses some of the key cytokines implicated in neuropathic pain.
This chapter explores the cellular and genetic mechanisms important in the development of neuropathic pain and other forms of chronic pain related to the phenomenon of sensitization. Peripheral sensitization contributes to pain hypersensitivity found at the location of tissue damage and/or inflammation. The chapter reviews the events that underlie pain as well as the anatomical and pharmacological basis for nociceptive sensations and chronic pain. Nociceptor excitation via various transient receptor potential (TRP) channels can result from a number of contributing processes. Transduction of mechanical, thermal, and chemical stimuli begins with membrane depolarization, which, if sufficient, transforms into an action potential. There are three classes of cell surface proteins at the sensory neuron important for sensory transduction: ion channels, metabotropic G protein-coupled receptors (GPCRs), and receptors for neurotrophins or cytokines. An important concept in central modulation of pain is the central inhibitory pathways and networks.
Tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs) (venlafaxine, duloxetine) are recommended as the first-line agents for peripheral neuropathic pain, especially for painful polyneuropathy, the other first-line options being gabapentinoids and topical lidocaine. Tricyclic antidepressants became a mainstay in the management of neuropathic pain before their mechanisms were elucidated and before the advent of systematic ways to evaluate their efficacy. Venlafaxine and duloxetine should be used with caution in patients with a history of mania, seizures, or bleeding tendency. Due to risk of excessive serotoninergic effect, they should be used with caution in patients receiving concomitant selective serotonin reuptake inhibitor (SSRI) or tramadol treatment. When selecting the treatment for an individual patient, comorbid conditions and their medications need to be taken into account. More detailed information of the effects of pharmacological agents on various symptoms of neuropathic pain and sensory profiles may guide drug selection in the future.
This chapter reviews an important mediator and its associated factors, the Toll-like receptors (TLRs). It examines the possible role that TLRs serve in neuroimmune interactions within both the central and peripheral nervous systems. The chapter focuses on Toll-like receptor 4 (TLR4) as this TLR appears to contribute directly to neurological pathologies such as neuropathic pain and opioid-induced hyperalgesia, as well as epilepsy. Inflammation in the absence of infection contributes to both injury and disease processes in the nervous system. There are many similarities between the mediators and changes in synaptic connectivity between neuropathic pain and epilepsy. Epileptic seizure conditions are routinely characterized as a neurocentric disease due in large part to the abnormally excessive or synchronous neuronal activity in the brain. The opioid family of drugs, though potent analgesics, are known to be only partially effective in treating neuropathic pain due in large part to the myriad of side effects.
This chapter describes commonly used peripheral nerve injury models of neuropathic pain. It introduces the central, non-traumatic and orofacial models of neuropathic pain. Neuropathic pain of central origin is observed clinically after traumatic incidents, such as stroke or spinal cord injury (SCI). An important consideration is that the pain experience, in humans and animals, has both sensory and emotional dimensions. The focus on nociception in pain research has been associated with the clinical failure of several potential pain medicines. An understanding of both sensory and affective dimensions of pain may improve translational research. Further, interpretations made from animal nerve injury models should be considered in the context of gender, age, and species/strain studied. Finally, it appears that no animal nerve injury model is without limitations, therefore, behavioral, physiological, and biochemical studies can only speculate on the relevance of experimental findings to human neuropathic pain.
Over the past 150 years, regional post-traumatic pain has had various appellations, most recently complex regional pain syndrome (CRPS) and post-traumatic neuralgia (PTN). CPRS appears to be a complex endophenotype of PTN that involves neurogenic inflammation as well as pain. There is increasing evidence that peripheral and central inflammatory cascades triggered by nerve injuries contribute to CRPS and perhaps PTN as well. PTN and CRPS often spread beyond classic individual nerve territories, although when patients are asked to outline the epicenter, or most abnormal area, this frequently identifies a specific nerve injury. The most dramatic CRPS and PTN-associated movement abnormality is fixed distal dystonia. Nerve conduction studies and electromyography are useful in documenting and localizing peripheral nerve damage. Currently, four classes of medications are primary options for chronic CRPS/PTN: tricyclics and serotonin-noradrenaline reuptake inhibitors; opioids; gabapentinoids; and topical or systemic local anesthetics.
This chapter summarizes a standard approach to identifying neuropathic pain for the clinician. For neuropathic pain, and for the condition of complex regional pain syndrome (CRPS) especially, the six Ss should be queried when obtaining details regarding the affected region. A useful tool to rapidly and accurately localize sources of chronic pain and assist in the diagnosis of causes of neuropathic pain is a pain diagram. The examination of a chronic pain patient should start with an appropriate and directed general examination including a neurological examination. Quantitative sensory testing (QST) provides indirect information used to evaluate underlying sensory function abnormalities using only small, portable tools and with less time requirement than protocols developed by the German Neuropathic Research Network. In the future, bedside QST is expected to continue to play a role in determining potential pain mechanisms to help direct further evaluation and treatment.
Neuropathic pain is present in approximately 20-30% of cancer patients with pain. The pathological mechanisms responsible for neuropathic pain are multifactorial. Assessment of neuropathic pain is crucial to appropriate management. Several pain scales were developed for patients with cancer pain. A meticulous neurology examination is helpful to evaluate thoroughly cancer patients with neuropathic pain. The pharmacological management of neuropathic cancer pain has recently been reviewed. Tramadol, codeine, and dihydrocodeine are recommended for the treatment of mild-to-moderate cancer pain intensity. The use of an analgesic ladder should be individualized with appropriate application of supportive drugs (e.g. laxatives and antiemetics) for the prevention and treatment of opioid adverse effects. Non-pharmacological measures, such as radiotherapy and invasive procedures (nerve blockades and neurolytic blocks) should also be used as required. In patients with very severe neuropathic pain, a combination of opioids and N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) are recommended.
Neuropathic pain after spinal cord injury (SCI) is a type of central neuropathic pain and is a frequent complication of spinal injury which is often refractory. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying neuropathic pain mechanisms. A major inhibitory system related to pain is opioid receptor mediated analgesia. In neuropathic pain, N-methyl-d-aspartate (NMDA) receptor activation increases excitation in the pain transmitting systems. Recent advances in pain research indicate multiple mechanisms, including many components of peripheral and central sensitization mechanisms, underlying the initiation and maintenance of neuropathic pain. Neurosurgical interventions may be treatment options in patients with poor pain control despite pharmacotherapy. Besides the effectiveness of a treatment, the adverse event profiles of these analgesics have to be considered before starting therapy or combining different agents.
Neuropathic pain is a chronic and disabling syndrome with complex pathogenesis. It has been suggested that the function of glutamate transporters (GLTs) has a major role in the development of neuropathic pain. This study was performed to evaluate various doses of ceftriaxone, a beta-lactam antibiotic, on the symptoms in the rat chronic constriction injury (CCI) model of neuropathic pain. This drug has been recently introduced as a selective up-regulator and activator of GLT1.
Neuropathy was induced in adult male Wistar rats and animals were treated intraperitoneally with 100–400 mg/kg of ceftriaxone for seven consecutive days immediately after surgery. Gabapentin (100 mg/kg, i.p.) was used as a reference drug. von Frey filaments, acetone drop and radiant heat methods were used to assess mechanical allodynia, thermal allodynia and thermal hyperalgesia, respectively.
Ceftriaxone in the repeated doses for 7 days showed significant antiallodynic and antihyperalgesic effects especially at a dose of 200 mg/kg twice a day.
The results suggest that ceftriaxone as a modulator of glutamate uptake could provide beneficial effects in the treatment of chronic neuropathic pain, especially allodynia that is less sensitive to the most available drugs.
The specific classification of pain states can help guide therapeutic approaches, and often clinical pain states are complex and involve multiple mechanisms. The choice of drug treatment for acute pain is typically a function of the severity of the pain. The treatment of inflammatory pain typically focuses on reducing the inflammation. Unlike inflammatory pain, the current approved treatments for neuropathic pain focus on treating the symptoms and not necessarily the underlying causes. To better understand the role of translational medicine in the development of pain treatments, it is useful to have a general understanding of the drug discovery process for pain drugs with particular emphasis on the use of animal models that currently play a major role in identifying candidate molecules for clinical trials. In pain research the most commonly used neuroimaging techniques are functional magnetic resonance imaging (fMRI) and positron emission tomography (PET).
One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia–neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia–neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia–neuron interactions in the pathobiology of neuropathic pain.