Chronic pain alters drug self-administration: implications for addiction and pain mechanisms

This review article focuses on the impact that the presence of pain has on drug self-administration in rodents, and the potential for using self-administration to study both addiction and pain, as well as their interaction. The literature on the effects of noxious input to the brain on both spinal and supraspinal neuronal activity is reviewed as well as the evidence that human and rodent neurobiology is affected similarly by noxious stimulation. The convergence of peripheral input to somatosensory systems with limbic forebrain structures is briefly discussed in the context of how the activity of one system may influence activity within the other system. Finally, the literature on how pain influences drug-seeking behaviors in rodents is reviewed, with a final discussion of how these techniques might be able to contribute to the development of novel analgesic treatments that minimize addiction and tolerance.     

Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia

A cell can regulate how it interacts with its external environment by controlling the number of plasma membrane receptors that are accessible for ligand stimulation. G-protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptors and have a significant role in physiological and pathological processes. Much research effort is now focused on understanding how GPCRs are delivered to the cell surface to enhance the number of 'bioavailable' receptors accessible for activation. Knowing how such processes are triggered or modified following induction of various pathological states will inevitably identify new therapeutic strategies for treating various diseases, including chronic pain. Here, we highlight recent advances in this field, and provide examples of the importance of such trafficking events in pain.     

Glutamate receptors and persistent pain: targeting forebrain NR2B subunits

Glutamate is the fast excitatory transmitter in mammalian brains. It binds to two major classes of glutamate receptors: ionotropic and metabotropic receptors. Ionotropic receptors contain three subtype receptors, including N-methyl-d-aspartate (NMDA) receptors. Activation of NMDA receptors is important for initiating long-lasting changes in synapses. In the forebrain structures that are known to contribute to the formation and storage of information, NMDA receptors have an important role in persistent inflammatory pain by reinforcing glutamate sensory transmission. Mice with enhanced forebrain NMDA receptor function demonstrate selective enhancement of persistent pain and allodynia. Drugs targeting NMDA NR2B subunits in the forebrain could serve as a new class of medicine for controlling persistent pain in humans.     

Chronopharmacokinetics: implications for drug treatment.

Nearly all functions of the human body are organized across the 24 hours of the day. This is also true for functions involved in the regulation of pharmacokinetics such as gastric absorption and emptying, gastro-intestinal perfusion, and liver and kidney functions. Several clinical studies, performed in a cross-over design, have provided evidence that the pharmacokinetics of mainly lipophilic drugs can be circadian phase-dependent. These studies show that after oral dosing, peak drug concentration (Cmax) is, in general, higher or time-to-peak (tmax) shorter after morning, compared with evening application. A few studies performed with both immediate-release and sustained-release preparations (isosorbide-5-mononitrate, nifedipine) gave evidence that only the immediate-release formulation displayed circadian time-dependent pharmacokinetics, but not the sustained-release form. Most importantly, pharmacodynamic studies performed in parallel revealed that the effects, as well as the dose-response relationship, can be circadian phase-dependent, an observation which has an impact on pharmacokinetic/pharmacodynamic modelling. Moreover, this can be of relevance because the onset of certain diseases (e.g., bronchial asthma, coronary infarction, angina pectoris, rheumatic complaints) is not randomly distributed across the 24-h scale. In conclusion, there is now convincing evidence that the time-of-day has to be taken into account both in clinical pharmacokinetic and pharmacodynamic studies.     

Heterodimerisation of G protein-coupled receptors: implications for drug design and ligand screening

Importance of the field: In recent times many G protein-coupled receptors (GPCRs) have been shown to dimerise/oligomerise and, in some cases, such structural organization has been found to be essential for receptor function or to play a modulatory role in living cells. The fact that these complexes may display differential pharmacology through, for example, the formation of a new binding pocket or signalling properties, as well as different functions or regulation in physiological tissues, offers novel opportunities for drug discovery. As a consequence, it seems necessary to develop new approaches suitable for GPCR heterodimer identification and selective ligand screening. Areas covered in this review: This review gives an overview of new strategies that have been developed in an effort to incorporate the possibilities added by GPCR hetero-oligomerisation on the screening of compounds as drug candidates. What the reader will gain: The reader will gain a wider knowledge about how the current understanding of GPCR oligomeric structure and function has mandated that hetero-oligomeric receptors must be considered as novel targets in the identification of future lead compounds. Take home message: For the improvement of novel drug discovery, more structural and functional information on the process of receptor oligomerisation is needed, and the realisation that the function of GPCRs can be greatly influenced by other interacting receptors or proteins also demands consideration in the lead-compound developing process in order to achieve better therapeutic agents.     

Structural biology of insulin and IGF1 receptors: implications for drug design

Type 2 diabetes mellitus -- in which the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose -- is an increasingly common disorder. Prospective clinical studies have proven the benefits of tighter glucose control in reducing the frequency and severity of complications of the disease, leading to the advocation of earlier and more aggressive use of insulin therapy. Given the reluctance of patients with type 2 diabetes to inject themselves with insulin, orally active insulin mimetics would be a major therapeutic advance. Here, we discuss recent progress in understanding the structure-function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy.     

Prostanoids in nociception and pain

Prostaglandins are lipid mediators produced by cyclooxygenases from arachidonic acid, which serve pivotal functions in inflammation and pain. Inhibition of their production is the major analgesic mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs)-but also the source of most of their unwanted effects. While the development of selective inhibitors of inducible cyclooxygenase (COX)-2 (so called coxibs) has greatly reduced gastrointestinal side effects, the recent disappointment about a potential cardiovascular toxicity of COX-2-selective inhibitors has boosted interest in alternative targets. The discovery of several prostaglandin synthases and of distinct prostaglandin receptors has unraveled an unforeseen diversity within the prostanoid synthetic pathway. Behavioral and electrophysiological work in particular with genetically engineered mice meanwhile provides new clues to the role of different prostaglandins, prostaglandin synthases and prostaglandin receptors in pain pathways.     

Emerging drug targets for pain treatment

In eukaryotes, many translation inhibitors have been widely used as bioprobes to evaluate the contribution of translation to signaling pathways and cellular functions. Several types of translation inhibitors are also known to trigger the activation of the mitogen-activated protein kinase superfamily in an intracellular mechanism called ribotoxic stress response. This perspective focuses on the biological properties of recently identified translation inhibitors that trigger ribotoxic stress response, particularly glutarimides as well as triene-ansamycins.     

Glutamate receptors and Parkinson's disease: opportunities for intervention

Parkinson's disease is a debilitating neurodegenerative movement disorder that is the result of a degeneration of dopaminergic neurons in the substantia nigra pars compacta. The resulting loss of striatal dopaminergic tone is believed to underlie a series of changes in the circuitry of the basal ganglia that ultimately lead to severe motor disturbances due to excessive basal ganglia outflow. Glutamate plays a central role in the disruption of normal basal ganglia function, and it has been hypothesised that agents acting to restore normal glutamatergic function may provide therapeutic interventions that bypass the severe motor side effects associated with current dopamine replacement strategies. Analysis of the effects of glutamate receptor ligands in the basal ganglia circuit suggests that both ionotropic and metabotropic glutamate receptors could have antiparkinsonian actions. In particular, NMDA receptor antagonists that selectively target the NR2B subunit and antagonists of the metabotropic glutamate receptor mGluR5 appear to hold promise and deserve future attention.     

Ubiquitination of g protein-coupled receptors: functional implications and drug discovery

G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development.     

KCNQ potassium channels: drug targets for the treatment of epilepsy and pain

Epilepsy and neuropathic pain are disorders characterised by excessive neuronal activity. These disorders are currently managed by drugs that are capable of dampening neuronal excitability, including voltage-gated sodium channel blockers, voltage-operated calcium channel modulators and modulators of inhibitory GABAergic neurotransmission. However, these drugs are rarely 100% efficacious and their use is often associated with limiting side effects. Thus, there is a clear medical need for novel agents to treat these diseases. One potential mechanism that has not yet been exploited is potassium (K⁺) channel opening. A significant (and growing) body of genetic, molecular, physiological and pharmacological evidence now exists to indicate that KCNQ-based currents represent particularly interesting targets for the treatment of diseases such as epilepsy and neuropathic pain. Evidence supporting these K⁺ channels as novel drug targets will be reviewed in the following article. Worldwide patent activity relating to KCNQ channels and KCNQ-modulating drugs and their uses will also be summarised.     

神经性疼痛和癫治疗新药普瑞巴林

美国FDA于2004年批准普瑞巴林作为治疗糖尿病性周围神经性疼痛和带状疱疹神经痛的药物。本文综述了近年来的相关临床研究情况,并总结了普瑞巴林的药理学、药动学、疗效及耐受性。     

Current concepts of the pathogenesis of acne: implications for drug treatment

The pathogenesis of acne is complex, with strong evidence supporting the involvement of sebaceous hyperplasia, follicular hyperkeratinisation, bacterial hypercolonisation, as well as immune reactions and inflammation. High sebum concentrations and follicular hyperkeratinisation lead to a change of the follicular milieu with consecutive proliferation of bacteria, chiefly Propionibacterium acnes. This leads to further increased production of the pro-inflammatory cytokines interleukin-1alpha and tumour necrosis factor alpha by T cells and keratinocytes, leading to proliferation of both cell types. Follicular keratinocytes fail to differentiate by apoptosis and produce hypergranulosis similar to the impermeable skin outer layer, resulting in the formation of microcomedones. Further inflammatory responses lead to the development of increasing degrees of severity in inflammatory forms of acne.Retinoids aid the differentiation and reduce the hyperproliferation of keratinocytes, and can inhibit the migration of leucocytes. Combination therapy using retinoids plus benzoyl peroxide or antibacterials can treat existing acne lesions faster than the individual agents alone and can also prevent the development of new lesions. The new retinoids (e.g. adapalene) have not only the typical potent comedolytic activity but also anti-inflammatory effects. When added to antibacterial therapy, topical retinoids demonstrate faster and significantly greater reduction of inflammatory acne lesions and comedones than antibacterials alone.     

Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia

Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.     

Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain

Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-D-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.     

Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain

Neuropathic pain remains a major clinical problem and a therapeutic challenge because existing analgesics are often ineffective and can cause serious side effects. Increased N-methyl-d-aspartate receptor (NMDAR) activity contributes to central sensitization in certain types of neuropathic pain. NMDAR antagonists can reduce hyperalgesia and allodynia in animal models of neuropathic pain induced by nerve injury and diabetic neuropathy. Clinically used NMDAR antagonists, such as ketamine and dextromethorphan, are generally effective in patients with neuropathic pain, such as complex regional pain syndrome and painful diabetic neuropathy. However, patients with postherpetic neuralgia respond poorly to NMDAR antagonists. Recent studies on identifying NMDAR-interacting proteins and molecular mechanisms of increased NMDAR activity in neuropathic pain could facilitate the development of new drugs to attenuate abnormal NMDAR activity with minimal impairment of the physiological function of NMDARs. Combining NMDAR antagonists with other analgesics could also lead to better management of neuropathic pain without causing serious side effects.     

Peripheral metabotropic glutamate receptors as drug targets for pain relief

The relatively new family of G-protein-coupled metabotropic glutamate receptors (mGluRs) is comprised of eight cloned subtypes, which are classified into three groups based on their sequence homology, signal transduction mechanisms and receptor pharmacology. It is now well-established that mGluRs in the central nervous system are essential for neuroplasticity associated with normal brain functions but are also critically involved in various neurological and psychiatric disorders. Recent anatomical and behavioural evidence suggests an important role of mGluRs in peripheral tissues in animal models of inflammatory and neuropathic pain. Once the cellular effects of peripheral mGluR activation and inhibition are better understood, certain peripheral mGluR subtypes may become important novel therapeutic targets for the relief of pain associated with peripheral tissue injury. Peripherally acting drugs that modulate nociceptive processing through mGluRs should have the advantage of lacking the central side effects commonly observed with drugs interfering with glutamatergic transmission in the central nervous system.     

Neuropathic pain: strategies in drug discovery and treatment

Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. In contrast to acute nociceptive pain, the cascade of events that arise following peripheral nerve injury leads to a maintained abnormality in the sensory system, resulting in an abnormal pain phenomenon that can be grossly debilitating. At present, there are very few effective and well-tolerated therapies for neuropathic pain. The development of animal models and constant progress in the understanding of the basic pathophysiology of neuropathic pain has led to multifarious drug targets and treatment options. The most effective agents are use-dependent inhibitors of Na⁺ channels, namely phenytoin, lamotrigine and carbamazepine. Owing to an effect of increase in the serotonin and various other biogenic amine levels on the pain modulating system, various classes of antidepressants including selective serotonin re-uptake inhibitors and selective noradrenaline re-uptake inhibitors are being used clinically. Modulation of Ca²⁺ channels is another useful approach for the treatment of neuropathic pain. In particular, the modulation of N-type Ca²⁺ channels, which are expressed primarily in central and peripheral nervous tissues, has been the subject of greatest interest. In view of the above, this review discusses the various strategies and approaches to novel drug discovery and pharmacotherapy of neuropathic pain syndromes.     

Animal models and peripheral nociception tests for the study of neuropathic pain

Neuropathic pain associated with abnormal tactile and thermal responses that are extraterritorial to the injured nerve is known to be difficult to diagnose and treat because of clinical observation of limited responsiveness to opioids and non-steroidal anti-inflammatory drugs. To reproduce the different pathological changes observed in neuropathic pain patients, several laboratory animal models have been proposed. Recent studies using such models suggest the involvement of neuronal plasticity in pain pathways through nociceptive neurons. Our new experimental model using specific pain-producing molecules that clearly distinguish three different nociceptive fibers from each other reproduces neuropathic pain-like hyperalgesia and less sensitivity to morphine. After nerve injury, the nociceptive responses through type I neurons, which are polymodal C-fibers and drive NK1-receptor mechanisms in spinal pain transmission, were completely lost, but without changes in type II ones, which are polymodal C-fibers and drive NMDA receptor-mechanisms, while type III ones, which are capsaicin-insensitive (possibly A-fibers) and drive NMDA-receptor mechanisms, were markedly enhanced. Such pain transmission switch mechanisms are clearly consistent with clinical effectiveness including less sensitivity to morphine and more sensitivity to NMDA-antagonists. This article also presents currently used methods for experimental neuropathic pain models.