Neuropathic pain causes

INVOLVEMENT OF INFLAMMATORY MEDIATORS IN NEUROPATHIC PAIN CAUSED BY VINCRISTINE... 

Elucidation of the mechanism of neuropathic pain caused by vincristine is required because long-term treatment with this anticancer agent often causes neuropathic pain. We refer to the involvement of inflammatory mediators in vincristine-induced neuropathic pain in this review. 

Immune-modulating agents that prevent activation of immune cells and/or the inhibitory agents of inflammatory cytokines could prevent the neuropathic pain caused by vincristine. These agents could increase the tolerability of vincristine when used for the treatment of leukemia and lymphoma. 

Vincristine, a vinca-alkaloid, prevents proliferation of tumor cells through the inhibition of tubulin polymerization. Vincristine is used as an anticancer agent for leukemia and lymphoma (Himes etal, 1976 Owellen etal., 1976). Clinical use of vincristine is often limited by its adverse effects, which include painful peripheral neuropathy (i.e., neuropathic pain) (Casey et al., 1973 Sandler et al., 1969). Elucidation of the detailed mechanism of neuropathic pain caused by vincristine is needed to improve quality-of-life for patients, and to make vincristine more tolerable for cancer treatment. 

Experimental models of neuropathic pain caused by repeated systemic treatment of vincristine were established to clarify therapeutic targets and potential therapeutic agents (Authier etal, 1999 Tanner etal, 1998). Studies characterized neuropathic pain caused by vincristine, and indicated that the involvement of inflammatory cytokines was similar to neuropathic pain induced by nerve injury (Kiguchi et al., 2008a,b). 

We focus on the aspects of neuropathic pain caused by vincristine. We refer to the roles of inflammatory cytokines, which may be critical in the development and maintenance of neuropathic pain. 

The detailed molecular mechanism of neuropathic pain caused by repeated systemic injection of vincristine is poorly understood. In general, systemically injected vincristine poorly penetrates into the CNS because of the blood—brain barrier (BBB) (Calabresi and Parks, 1985). It is thought that vincristine may act on... 

Fig. 1. Peripheral and central mechanism of neuropathic pain caused by vincristine. The upper diagram shows the effect of vincristine on the peripheral nervous system (comprising Schwann cells and the dorsal root ganglion (DRG)) and the involvement of interleukin (IL)-6 derived from infiltrating macrophages in neuropathic pain caused by vincristine. The lower diagram shows the effect of vincristine on the central nervous system, and the involvement of tumor necrosis factor-a (TNF-a) derived from activated microglia and astrocytes in neuropathic pain caused by vincristine.

Finally, the synthetic cannabinoid CT-3 was compared (Karst et al. 2003) with placebo in a randomised, double-blind, crossover trial in 21 patients with chronic neuropathic pain (cause unspecified). In 1-week treatment periods, patients received 4 capsules (10 mg CT-3 or placebo) daily in divided doses for the first 4 days and 8 daily for the following 3 days. Pain VAS scores were significantly improved by CT-3 in comparison with placebo (p = 0.02), although there was no dose-response relationship. Unwanted effects (most commonly dry mouth and tiredness) occurred more frequently following CT-3. The authors concluded that this preliminary evaluation suggested that CT-3 was effective in reducing chronic neuropathic pain. 

Neuropathic pain is initiated or caused by a primary lesion in the peripheral or central nervous system. The causative agent may be trauma, nerve-invading cancer, herpes zoster, HIV, stroke, diabetes, alcohol or other toxic substances. Neuropathic pain is refractory to most analgesic drugs. Altered sodium channel activity is characteristics of neuropathic pain states. 

Neuropathic pain states are thought to be generated in the peripheral sensory neurons by events within the nerve itself and so are independent of peripheral nociceptor activation. Damage to peripheral nerves can be caused by a number of pathological, metabolic and viral causes. According to the terminology guide of the International... 

Association of Pain, neuropathic pain is defined as pain initiated or caused by a primary lesion, dysfunction in the nervous system". Neuropathy can be divided broadly into peripheral and central neuropathic pain, depending on whether the primary lesion or dysfunction is situated in the peripheral or central nervous system. In the periphery, neuropathic pain can result from disease or inflammatory states that affect peripheral nerves (e.g. diabetes mellitus, herpes zoster, HIV) or alternatively due to neuroma formation (amputation, nerve transection), nerve compression (e.g. tumours, entrapment) or other injuries (e.g. nerve crush, trauma). Central pain syndromes, on the other hand, result from alterations in different regions of the brain or the spinal cord. Examples include tumour or trauma affecting particular CNS structures (e.g. brainstem and thalamus) or spinal cord injury. Both the symptoms and origins of neuropathic pain are extremely diverse. Due to this variability, neuropathic pain syndromes are often difficult to treat. Some of the clinical symptoms associated with this condition include spontaneous pain, tactile allodynia (touch-evoked pain), hyperalgesia (enhanced responses to a painful stimulus) and sensory deficits. 

There are important inhibitory systems built into the control of events following C-fibre stimulation. Thus, during peripheral noxious stimulation, spinal mechanism, driven by NMDA-receptor-mediated activity, can become active to damp down further neuronal responses, the purine, adenosine (see Chapter 13), appears to be involved in this type of control and has been reported to be effective in humans with neuropathic pain. It is thought that the depolarisations caused by activation of the NMDA receptor increase the metabolic demand on neurons and so ATP utilisation increases. ATP then is metabolised to adenosene and the purine then acts on its inhibitory Ai receptor in the... 

A broad variety of diseases may cause neuropathic pain 935 Injured axons may develop spontaneous and repetitive firing known as ectopic activity 935 Sensory neurons transform their phenotype 936 Spinal disinhibition allows more nociceptive signal input 936 Peripheral nerve injury provokes a marked neuroimmune reaction 937... 

A broad variety of diseases may cause neuropathic pain. The majority of diseases associated with neuropathic pain involve the peripheral nervous system. These diseases include traumatic injuries hereditary, metabolic, inflammatory or paraneoplastic neuropathies and infections. However, neuropathic pain can also be caused by injuries or disorders affecting the spinal cord or the brain (central neuropathic pain) tumors stroke epilepsy and neurodegenerative disorders [20]. Genetic factors appear to contribute to inter-individual differences in the susceptibility to neuropathic pain. 

There are two major classes of pain medications, nonopioids and opioids. The nonopioids used to treat mild pain include agents such as acetaminophen, both steroid and nonsteroidal antiinflammatory drugs (NSAIDs), and acetylsalicylic acid. Anticonvulsants suppress neuronal firing and are also helpful in neuropathic pain. Antiinflammatory agents (e.g., NSAIDs or corticosteroids) may be particularly helpful when bony involvement occurs and are often used for low-intensity pain. Steroids decrease inflammatory edema and are useful in cases of nerve and spinal cord compression, lymphedema, visceral pain caused by organ enlargement, and bone pain. Finally, short-term corticosteroid therapy may also produce euphoria (thus ameliorating less severe depressions) as well as reverse anorexia. 

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