Neurotrophic factors as novel therapeutics for neuropathic pain

Neuropathic pain is a chronic condition that is caused by injury to the nervous system. Unlike acute pain, which is protective, neuropathic pain persists and serves no useful purpose, and severely affects quality of life. However, present therapies have modest efficacy in most patients, are palliative rather than curative, and their side effects represent significant limitations. Tremendous progress has been made over the past decade in our understanding of the biology of pain sensory neurons. The recent discovery that neurotrophic factors play an important role in neuropathic pain indicates that these pathways could serve as novel intervention points for therapy. Moreover, neurotrophic factors have the potential to address the underlying pathophysiology of neuropathic pain, thereby halting or reversing the disease process.     

A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors

Recent evidence indicates that trophic factors can exert fast effects on neurones and so alter synaptic plasticity. Here, we focus on brain-derived neurotrophic factor (BDNF), which exerts a modulatory action at hippocampal synapses that are involved in learning and memory, and at the first pain synapse between primary sensory neurones and dorsal horn neurones. Hippocampal and sensory neurones share some properties for the release of endogenous BDNF. In the Schaffer collateral pathway of the hippocampus, binding of BDNF to high-affinity trkB receptors is essential for the induction of long-term potentiation, a specific type of synaptic plasticity. However, the consequences of BDNF binding to trkB receptors in the dorsal horn in relation to pain mechanisms are less well established and are considered in detail.     

GDNF and somatostatin in sensory neurones

Somatostatin (SOM) is a regulatory peptide produced throughout the central nervous system and in most major peripheral organs. In humans, the SOM stable analogue octreotide (OCT) is used to treat opioid-resistant pain. In animal models, SOM and OCT are analgesics and SOM released from the peripheral endings of sensory neurones exerts anti-inflammatory actions. The expression of SOM in sensory neurones can be modulated by the trophic factor glial-cell-line-derived neurotrophic factor (GDNF). Recent data show that GDNF modulates activity-induced release of endogenous SOM from both central and peripheral terminals of adult sensory neurones. This novel mechanism deserves exploration as a potential new therapeutic strategy to control two major features of inflammation: pain and leukocyte recruitment.     

Uncovering new pharmacological targets to treat neuropathic pain by understanding how the organism reacts to nerve injury

The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. One rational possibility for the pharmaceutical development of new drugs, including target identification, drug design and evaluation studies, could be to focus on mimicking what organism does to limit nerve damage or to enhance the regeneration of injured axons. Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.     

The role of tetrodotoxin-resistant sodium channels in pain states: are they the next target for analgesic drugs?

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral nervous system, is a condition that severely affects the quality-of-life of millions of individuals worldwide. The treatment of neuropathic pain is still an unmet medical need; however, recent advances in our understanding of mechanisms underlying the perception and transmission of painful stimuli offer significant potential for improvement of therapies directed to neuropathic pain. Ectopic activity in damaged and dysfunctional sensory afferents is believed to have a role in the generation and maintenance of neuropathic pain. One of the mechanisms underlying this ectopic firing involves abnormal modulation of voltage-gated sodium channels (NaVs) in the soma and axonal membranes of dorsal root ganglion (DRG) sensory neurons. In fact, NaV blockers have been clinically validated as treatments for neuropathic pain. However, current drugs are weak, non-selective inhibitors of NaVs with dose-limiting CNS and cardiovascular side effects that prevent their use in long-term therapy. Selective NaV tetrodotoxin-resistant channels (NaV 1.8 and NaV 1.9) are expressed exclusively in nociceptive neurons in the DRGs where they play a key role in normal and/or pathological pain sensation, providing an opportunity for the development of novel peripheral analgesics with a better safety profile.     

The effect of ABT-702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury

1. Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non-nucleoside adenosine kinase (AK) inhibitor, ABT-702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT-702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain. 2. Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane-anaesthetized rats. ABT-702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals. 3. ABT-702 produced inhibition of the postdischarge, wind-up and C-fibre evoked responses in both carrageenan and nerve-injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT-702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT-702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance. 4. Protection of endogenous adenosine by ABT-702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine-mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.     

Mechanisms of sympathetic pain.

In some chronic pain states, notably causalgia and reflex sympathetic dystrophy, activity in sympathetic efferent neurones can exacerbate the pain and sympathectomies relieve it. These patients are said to have sympathetically maintained pain (SMP). In normal tissue, activity in postganglionic sympathetic efferents does not produce pain, nor is it capable of activating nociceptive sensory neurones. It can, however, induce modest firing in some mechanoreceptors. SMP is often held to result from a vicious circle of events which include changes in peripheral and central somatosensory processes, and most importantly a positive feedback element in the form of sympathetic efferent neurones which, by activating sensory neurones in the periphery, completes the vicious circle. Several specific hypotheses have been advanced as to the primary pathophysiological cause of pain in these patients. Suggestions, largely deriving from observations on animal models, include: ephaptic transmission, adrenergic receptors on sensory neurones, indirect coupling of sympathetic and sensory neurones, sensitization of nociceptive afferents, and, in the central nervous system, sensitization of dorsal horn neurones. All these suggestions have some supporting evidence, but none are able to adequately explain all the disturbances seen in patients with SMP.     

The therapeutic potentials of neurotrophic factors for diseases of the nervous system

Neurotrophic factors are secreted proteins that regulate the long-term survival and differentiation of neurones in the peripheral and central nervous systems (PNS and CNS). Their profound effects on the structural integrity of the nervous system have led to intense interest in the potential use of the factors as therapeutic agents for neurodegenerative diseases. In the present review, we summarise the current data on the physiological role of these proteins based on in vitro investigations and animal models, and discuss their clinical potential as therapeutic agents in the treatment of neurological disorders. A rationale for neurotrophic factor therapy can be built for a specific neurological disease once a particular neurotrophic factor is identified to regulate vulnerable neurones in the affected areas. Progress has been made in the use of neurotrophic factors as an alternative therapy to conventional drug treatment, particularly for Alzheimer’s disease, Parkinson’s disease and peripheral neuropathy. Production of chimeric neurotrophins may combine the beneficial aspects of a number of neurotrophic factors. Delivery of exogenous protein factors to the CNS remains one of the major obstacles for trophic factor therapy. Second generation approaches (including transplantation of genetically engineered cells, direct gene transfer into the brain and pharmacological manipulation of the levels of endogenous neurotrophic factors) may prove to be effective in overcoming the technical problems surrounding direct CNS delivery. The discovery of new trophic molecules and development of novel delivery methods represent two important aspects of neurotrophic therapy for neurodegenerative diseases.     

Prospects for the treatment of Parkinson’s disease using neurotrophic factors

Parkinson’s disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific ‘dopaminotrophic’ effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.     

Prospects for the treatment of Parkinson's disease using neurotrophic factors

Parkinson's disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of alpha-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific 'dopaminotrophic' effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.     

胶质细胞源性神经营养因子与神经病理性疼痛

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是神经营养因子家族成员之一,GD-NF对中枢和周围神经系统多种神经元的生长、发育、分化、维持和损伤修复起重要作用。另外,GDNF还参与中枢和外周水平神经病理性疼痛的形成和发展。该文主要就GDNF和神经病理性疼痛的研究作一简要综述。     

Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.

Pain therapeutics discovered by molecular mining of the expressed genome of Australian predatory cone snails are providing lead compounds for the treatment of neurological diseases such as multiple sclerosis, shingles, diabetic neuropathy and other painful neurological conditions. The high specificity exhibited by these novel compounds for neuronal receptors and ion channels in the brain and nervous system indicates the high degree of selectivity that this class of neuropeptides can be expected to show when used therapeutically in humans. A lead compound, ACV1 (conotoxin Vc1.1 from Conus victoriae), has entered Phase II clinical trials and is being developed for the treatment for neuropathic pain. ACV1 will be targeted initially for the treatment of sciatica, shingles and diabetic neuropathy. The compound is a 16 amino acid peptide [Sandall et al., 2003. A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo. Biochemistry 42, 6904-6911], an antagonist of neuronal nicotinic acetylcholine receptors. It has potent analgesic activity following subcutaneous or intramuscular administration in several preclinical animal models of human neuropathic pain [Satkunanathan et al., 2005. Alpha conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurons. Brain. Res. 1059, 149-158]. ACV1 may act as an analgesic by decreasing ectopic excitation in sensory nerves. In addition ACV1 appears to accelerate the recovery of injured nerves and tissues.     

Neuropathic pain and injured nerve: peripheral mechanisms.

Injury to sensory axons often has the paradoxical effect of inducing positive sensory disturbances; paraesthesias and chronic neuropathic pain. Such symptoms can be at least partially understood in terms of pathophysiological changes that occur in the electrical excitability of the injured sensory neuron. These changes result in the generation of an abnormal ongoing and evoked discharge, originating, alternatively, at various ectopic neural pacemaker sites. Many of the most effective therapeutic modalities recommended for neuropathic pain act by reducing this ectopic neural discharge.     

Methods for Evaluating Sensory,Affective and Cognitive Disorders in Neuropathic Rodents

The animal models of neuropathic pain that faithfully reproduce the symptoms that occur in humans are a fundamental tool for understanding the mechanisms underlying the disease, identifying new targets, and developing effective drugs. So far, the studies aimed at describing the animal models of neuropathic pain have been focused mainly on the sensory symptoms associated with the disease consisting of mechanical allodynia and hyperalgesia, cold allodynia and hyperalgesia, and heat hyperalgesia. However, affective and cognitive comorbidities occur in patients suffering from neuropathic pain, arising in a closely associated and dependent manner on the sensory symptoms. The same occurs in animal models of neuropathic pain in which anxiety- and depressive-like behaviors and cognitive disorders are observable at different time points from the induction of neuropathy. Today there are several tests available that exploit different paradigms in rodents for measuring sensorial, affective, and cognitive behavior. This review will describe those mainly used in the scientific community. The tests mainly used are based on the motor activity of the animals tested, so it is fundamental that it remains unaffected in the model used for inducing neuropathic pain. We hope that this review will be useful to the scientific community to direct the choice towards the best, most suitable, and simplest tests for the study of the sensory, affective, and cognitive symptoms associated with neuropathic pain.     

Retigabine: chemical synthesis to clinical application

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.     

Tetrodotoxin,a Potential Drug for Neuropathic and Cancer Pain Relief?

Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype Na_V1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype Na_V1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs.     

Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.     

Effects of lacosamide, a novel sodium channel modulator, on dorsal horn neuronal responses in a rat model of neuropathy

Various mechanisms underlie the complexity of neuropathic pain (pain due to disease of the somatosensory system), with each mechanism bearing a different order of relevance from one person and pain state to the next. Successful treatment is contingent on sound knowledge of underlying mechanisms that may occur at peripheral, spinal and/or supraspinal sites. In particular, ion channels throughout the nervous system are known to play an intimate part in neuropathic pain, and thus stand as good targets for analgesic drugs. Agents that modulate voltage-gated sodium channel function can reduce action potential propagation along sensory neurones to reduce the transmission and perception of nociceptive signals. Lacosamide is a functionalised amino acid that affects voltage-gated sodium channels in a novel way by enhancing the slow inactivating ‘braking’ state of these channels. To validate lacosamide's inhibitory efficacy in vivo, we unilaterally ligated spinal nerves L5 and L6 in rats to induce a state of neuropathy, and on post-operative days 14-17 recorded evoked-responses of deep dorsal horn neurones before and after spinal or systemic lacosamide delivery. Lacosamide's effects on various measures in spinal nerve-ligated rats were compared to rats that underwent sham surgery. Our results show that neuropathy induced novel inhibitory effects of lacosamide on mechanical and electrical responses, and enhanced inhibitory effects on thermal responses after systemic or spinal administration, suggesting state-preference actions of lacosamide.     

The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain

The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB₂). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB₂ is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB₂ receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB₂ agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.     

Role of Neurotrophins in Neuropathic Pain

Neurotrophins (NTs) belong to a family of structurally and functionally related proteins, they are the subsets of neurotrophic factors. Neurotrophins are responsible for diverse actions in the developing peripheral and central nervous systems. They are important regulators of neuronal function, affecting neuronal survival and growth. They are able to regulate cell death and survival in development as well as in pathophysiologic states. NTs and their receptors are expressed in areas of the brain that undergo plasticity, indicating that they are able to modulate synaptic plasticity.Recently, neurotrophins have been shown to play significant roles in the development and transmission of neuropathic pain. Neuropathic pain is initiated by a primary lesion or dysfunction in the nervous system. It has a huge impact on the quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human well being. Neuropathic pain ranks at the first place for sanitary costs.Neuropathic pain treatment is extremely difficult. Several molecular pathways are involved, making it a very complex disease. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury. At present there are no valid treatments over time and neuropathic pain can be classified as an incurable disease.Nowadays, pain research is directing towards new molecular methods. By targeting neurotrophin molecules it may be possible to provide better pain control than currently available.