Current Drug Targets-CNS & Neurological Disorders - Volume 3, Issue 6, 2004

Voltage-gated sodium channels are highly specialized molecular transducers that play a significant role in the creation and transmission of electrical activity throughout the neuraxis. These ion channels are fundamentally involved in sensory neuron physiology and pathophysiology; a complete but localized suspension of their normal function can prevent all sensation - including that perceived as pain. Soft-tissue injuries that result in inflammation or direct damage to nerve fibers have each been shown to result in abnormal sodium channel function and, in many cases, to lead to pathological hyperexcitability in the sensory afferent nerves that innervate the injured dermatome or visceral organ. Abrogating abnormal activity whilst leaving normal sensation unaffected would represent a powerful approach to pain relief. This article reviews the evidence supporting abnormal sodium channel biology in various pathological contexts, the opportunities that this presents for novel therapeutics and progress towards realizing this goal.

This review focuses on the importance of voltage-gated calcium channels in modulating and controlling the function of peripheral and central neurons involved in nociceptive processing. We describe the different families of voltage-gated calcium channels that are expressed in pain pathway neurons, how the expression levels of calcium channel currents change in chronic pain conditions, and the validation of N-type, T-type, and P-type calcium channels as targets for the treatment of pain. The molecular mechanism of action is reviewed for the most prominent calcium channel-targeted drugs including gabapentin and ziconotide as well as antiepileptics administered off-label for the treatment of pain. We discuss how the major genetic, functional, and pharmacological differences between subtypes of neuronal calcium channels can be leveraged to identify new molecular targets and to discover and develop new therapeutic agents for the treatment of chronic pain syndromes.

Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of the peripheral terminals called nociceptor, and many kinds of ionotropic and metabotropic receptors are involved in this process. Capsaicin receptor TRPV1 is a nociceptor-spesific ion channel that serves as the molecular target of capsaicin. TRPV1 can be activated not only by capsaicin but also by noxious heat (with a thermal threshold >43°C) or protons (acidification), all of which are known to cause pain in vivo. Studies using TRPV1-deficient mice have shown that TRPV1 is essential for selective modalities of pain sensation and for thermal hyperalgesia. One mechanism underlying inflammatory pain which is initiated by tissue damage / inflammation and characterized by hypersensitivity is sensitization of TRPV1. In addition to TRPV1, there are five thermosensitive ion channels in mammals, all of which belong to the TRP (transient receptor potential) super family. These include TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. These channels exhibit distinct thermal activation thresholds (> 52°C for TRPV2, > ∼34-38°C for TRPV3, > ∼27-35°C for TRPV4, < ∼25-28°C for TRPM8 and < 17°C for TRPA1) and are expressed in primary sensory neurons as well as other tissues. Some of the thermosensitive TRP channels are likely to be involved in thermal nociception, since their activation thresholds are within the noxious range of temperatures.

A lack of inhibition, particularly that mediated by gamma-amino butyric acid (GABA), the main inhibitory transmitter of the central nervous system (CNS), is responsible for many pain states. Until recently, few GABA acting drugs were available and were prescribed mostly for relieving muscle spasms, anxiety and epilepsy, but rarely for pain. The basic metabolic pathway of GABA is well known and we are now beginning to understand the function of this neurotransmitter in the complex circuitry underlying pain, especially in the context of nerve injury. Analgesic compounds are now being developed targeting GABA transporters as well as GABA associated enzymes and receptors. Some GABA analogs act by inhibiting ion channels, a property that contributes to their analgesic effects. However, despite considerable progress in developing new compounds, the use of systemically acting GABAergic drugs is limited by unwanted side-effects on systems other than those involved in pain, and by the fact that in certain areas of the brain, GABA can enhance rather than reduce pain. The advent of new drugs targeting subtypes of GABA receptors and transporters and the possibility of using newly developed delivery systems, such as intrathecal pumps and viral vectors, to target specific areas of the nervous system will likely help circumvent these problems.

Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge to the clinicians. While the exact cause and pathology of this disorder is uncertain, it is thought that trigeminal neuralgia caused by irritation of the trigeminal nerve. This irritation results from damage due to the change in the blood vessels, the presence of a tumor or other lesions that cause the compression of the trigeminal root. The pain of trigeminal neuralgia is characterized by unilateral pain attacks that start abruptly and last for varying periods of time from minutes to hours. The quality of pain is usually sharp, stabbing, lancinating, and burning. The attacks are initiated by mild stimuli such as light touch of the skin, eating, chewing, washing the face, brushing the teeth, and exposure to wind. Although antiepileptic drug therapy may be beneficial in the treatment of trigeminal neuralgia, up to one-half of the patients become refractory or intolerant to these medications. At present there are few other effective drugs. In cases of lacking effect after pharmacotherapy, surgical options may be considered. Currently there is growing amount of evidence to suggest that the psychoactive ingredient in cannabis and individual cannabinoids may be effective in alleviating neuropathic pain and hyperalgesia. Evidence suggests that cannabinoids may prove useful in pain modulation by inhibiting neuronal transmission in pain pathways. Considering the pronounced antinociceptive effects produced by cannabinoids, they may be a promising therapeutic approach for the clinical management of trigeminal neuralgia.

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.