Current Pharmaceutical Design - Volume 11, Issue 23, 2005

Antidepressant drugs have been widely used for many years to treat neuropathic pain, despite the rationale for their use was still unclear. We review recent insights into their mechanism of action, focusing on central and peripheral analgesic actions. Beside the traditional monoaminergic hypothesis, other pharmacological actions have been studied: antidepressants interfere with the opioid system, interact with the NMDA receptors, and inhibit ion channel activity. Firm evidence from randomised controlled trials demonstrated that TCAs are the most effective drugs for treatment of different neuropathic pain conditions. They exhibit the lowest number needed to treat compare with all other drugs investigated. SSRIs failed to provide an adequate analgesia, due to their high selectivity. SSRIs are clearly less effective than TCAs (NNT: 6.7 vs 2.4) supporting the hypothesis that a balanced inhibition of noradrenaline and serotonin reuptake is more effective in relieving pain. On the basis of initial results Venlafaxine seems to be the most promising of the newer antidepressants as analgesic. Newer antidepressants show a better side effects profile, but further investigation are warranted to clarify their potential role in management of pain. Neuropathic pain remains a challenging condition to treat, as all currently available drugs fail to achieve adequate pain relief in a significant proportion of patients. TCAs should be currently considered the first choice in treatment of neuropathic pain and the gold standard against which to compare other potential new treatments.

Neuropathic pain is characterised by both positive (hyperalgesia and allodynia) and negative (sensory deficits) symptoms and remains intractable to many commonly used analgesics. Antiepileptics are increasingly utilised in the treatment of neuropathic pain. This class of drugs works via three major mechanisms of action in order to dampen neuronal hyperexcitability within the central nervous system: potentiation of GABA transmission, reduction of glutamatemediated excitatory transmission, and block of voltage-activated ion channels. The latter mechanism of action in particular, is exemplified by the success of the newer generation of antiepileptics such as lamotrigine and gabapentin in the clinical treatment of neuropathic pain symptoms. In the current review article, we will examine in detail, the antinociceptive effects of a diverse range of antiepileptics as tested in animal models of nerve injury. Where appropriate, we will compare these findings with their analgesic efficacy in the clinical treatment of neuropathic pain.

NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.

Neuropathic pain can be difficult to treat clinically, as current therapies involve partial effectiveness and significant adverse effects. Following the development of preclinical models for neuropathic pain, significant advances have been made in understanding the neurobiology of neuropathic pain. This includes an appreciation of the molecular entities involved in initiation of pain, the role of particular afferents (small and large diameter, injured and uninjured), and the contribution of inflammation. Currently, topical formulations of capsaicin (cream) and lidocaine (patch) are available for treating neuropathic pain in humans. Preclinical studies provide evidence that peripheral applications of opioids, α- adrenergic agents, and antidepressants also may be beneficial in neuropathic pain, and some clinical reports provide support for topical applications of such agents. An appreciation of the ability of drug application, to sites remote from the site of injury, to alleviate aspects of neuropathic pain will provide a significant impetus for the further development of novel topical analgesics for this condition.

Subtypes of tetrodotoxin resistant voltage-gated sodium channels are involved in the development of certain types of neuropathic pains. After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury. The facts that these sodium channels seem to exist in peripheral nerves only and that they can be blocked at the resting state (use-dependent block) offer the possibility to develop drugs, which selectively block these damaged, overexcited nerves. At the moment no such drugs are available. However, some of the most potent drugs that are currently used to manage neuropathic pain e.g. amitriptyline and other tricyclic antidepressants, also block these channels in addition to having several other mechanisms of action. Also most anticonvulsants that are used to alleviate neuropathic pain are sodium channel blockers. Lidocaine, the prototype drug, has been shown to be effective in peripheral neuropathic pain. Its use is limited by the fact that it cannot be administered orally. An oral local anesthetic type sodium channel blocker, mexiletine is an antiarrhythmic agent that is effective in neuropathic pain. However, effective doses may be difficult to achieve because of adverse effects.

Opiates lack potent analgesic efficacy in neuropathic pain although it is now generally accepted that the poor effect of these drugs reflects a reduction in their potency. Reduction of morphine antinociceptive potency was postulated to be due to the fact that nerve injury altered the activity of opioid systems or opioid specific signaling. Endogenous opioid systems were found to be represented in the regions involved in the nociception and are implicated in chronic pain. Opioid peptides biosynthesis and opioid receptors density in the nociceptive pathways and their functions change under various conditions associated with neuropathic pain following damage to the spinal cord and injury of peripheral nerves. Identification of a role of opioid systems in neuropathic pain and molecular and cellular mechanisms underlying these processes are of importance to understanding of the opioid action in neuropathic pain that will hopefully facilitate development of therapeutic strategies in which effectiveness of opioids in alleviation neuropathic pain is increased.

It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with anti-histamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-γ are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.

In chronic arthritis synovial inflammation is usually accompanied by bone erosion. Due to resulting structural damage, bone erosion is major reason for disability of RA patients. Thus, drug therapy in arthritis is not only focussed on the control of synovial inflammation but also on preserving bone from structural damage. Bone erosion in arthritis is a consequence of synovial osteoclast formation. Therapeutic approaches, which interfere with synovial osteoclastogenesis and/or osteoclast activation, are therefore of great interest. This review describes the pathomechanism of arthritic bone erosion, describes its cellular and molecular players and gives insights in current therapeutic tools to inhibit this process. Effects of blockade of tumor necrosis factor, interleukin-1 and receptor activator of NF-kB ligand are discussed. Arthritis and bone loss are two related conditions but they are not necessarily linked to each other. Thus, in case of shortlasting and self-limited disease, structural damage is highly unusual. One of the most intriguing examples is viral arthritis, which as in case of parvovirus infection is a polyarticular disease closely mimicking rheumatoid arthritis. However, parvoviral arthritis is always a self-limited condition and resolves without any structural damage. In contrast, chronic forms of arthritis, such as psoriatic arthritis or rheumatoid arthritis (RA) are usually destructive and lead to alteration of joint structure and functional impairment.

Nitric oxide (NO) plays role in a great range of important functions in the organism, such as vasodilatation, relaxation of muscles, neurotransmission, neuromediation, and host defense reactions. In the upper airways, nasal cavities and paranasal sinuses are the main sources of this biological mediator. Although the exact role of NO in nasal physiology remains poorly understood, the functions are thought to be host defense, ciliary motility and improved ventilation-perfusion ratio in the lungs by auto-inhalation. Low NO concentrations were reported in certain diseases such as primary ciliary dyskinesia, cystic fibrosis, and acute and chronic maxillary sinusitis whereas high concentrations were detected in upper airway infection, allergic rhinitis and nasal polyposis. Additionally this ubiquitous radical is being implicated in the regulation of cochlear blood flow, sensorineural hearing loss, middle ear effusions, and outer hair cell and vestibular functions. Solid tumors is another area where NO appears to have both tumor-promoting and tumorinhibiting effects. The presence of NO with high levels within the nose and paranasal sinuses makes it reasonable to believe that this pluripotent gas is involved in a variety of physiological as well as pathophysiological events in the airways. Although NO has an ever-increasing role in various areas related to the practice of otolaryngology, further research is required to understand fully the role of NO in the upper airways.

Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL- and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARα and PPARγ agonists, such as thiazolidinediones and fibrates, and PPARδ agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.