Current Neuropharmacology (v.11, #6)

Despite the myriad promising new targets and candidate analgesics recently identified in preclinical painstudies, little translation to novel pain medications has been generated. The pain phenotype in humans involves complexbehavioral alterations, including changes in daily living activities and psychological disturbances. These behavioralchanges are not reflected by the outcome measures traditionally used in rodents for preclinical pain testing, which arebased on reflexes evoked by sensory stimuli of different types (mechanical, thermal or chemical). These measures do notevaluate the impact of the pain experience on the global behavior or disability of the animals, and therefore only considera limited aspect of the pain phenotype. The development of relevant new outcomes indicative of pain to increase thevalidity of animal models of pain has been increasingly pursued over the past few years. The aim has been to translate“bedside-to-bench” outcomes from the human pain phenotype to rodents, in order to complement traditional painoutcomes by providing a closer and more realistic measure of clinical pain in rodents. This review summarizes anddiscusses the most important nonstandard outcomes for pain assessment in preclinical studies. The advantages anddrawbacks of these techniques are considered, and their potential impact on the validation of potential analgesics isevaluated.

Tissue Injury and Related Mediators of Pain Exacerbation by Fumimasa Amaya, Yuta Izumi, Megumi Matsuda, Mika Sasaki (592-597).
Tissue injury and inflammation result in release of various mediators that promote ongoing pain or painhypersensitivity against mechanical, thermal and chemical stimuli. Pro-nociceptive mediators activate primary afferentneurons directly or indirectly to enhance nociceptive signal transmission to the central nervous system. Excitation ofprimary afferents by peripherally originating mediators, so-called “peripheral sensitization”, is a hallmark of tissue injuryrelatedpain. Many kinds of pro-nociceptive mediators, including ATP, glutamate, kinins, cytokines and tropic factors,synthesized at the damaged tissue, contribute to the development of peripheral sensitization. In the present review we willdiscuss the molecular mechanisms of peripheral sensitization following tissue injury.

The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARshave raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology andpathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain.In particular, experiments in animal models suggest that PAR2 is important for visceral hypersensitivity. Moreover,endogenous PAR2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome,suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them,represent exciting targets for therapeutic intervention on visceral pain.

Chronic pain is a major therapeutic problem as the current treatment options are unsatisfactory with lowefficacy and deleterious side effects. Voltage-gated Ca2+ channels (VGCCs), which are multi-complex proteins consistingof α 1,β,γ, and α 2δ subunits, play an important role in pain signaling. These channels are involved in neurogenicinflammation, excitability, and neurotransmitter release in nociceptors. It has been previously shown that N-type VGCCs(Cav2.2) are a major pain target. U.S. FDA approval of three Cav2.2 antagonists, gabapentin, pregabalin, and ziconotide,for chronic pain underlies the importance of this channel subtype. Also, there has been increasing evidence that L-type(Cav1.2) or T-type (Cav3.2) VGCCs may be involved in pain signaling and chronic pain. In order to develop novel paintherapeutics and to understand the role of VGCC subtypes, discovering subtype selective VGCC inhibitors or methodsthat selectively target the inhibitor into nociceptors would be essential. This review describes the various VGCC subtypeinhibitors and the potential of utilizing VGCC subtypes as targets of chronic pain. Development of VGCC subtypeinhibitors and targeting them into nociceptors will contribute to a better understanding of the roles of VGCC subtypes inpain at a spinal level as well as development of a novel class of analgesics for chronic pain.

Electrical excitation of peripheral somatosensory nerves is a first step in generation of most pain signals inmammalian nervous system. Such excitation is controlled by an intricate set of ion channels that are coordinated toproduce a degree of excitation that is proportional to the strength of the external stimulation. However, in many diseasestates this coordination is disrupted resulting in deregulated peripheral excitability which, in turn, may underpinpathological pain states (i.e. migraine, neuralgia, neuropathic and inflammatory pains). One of the major groups of ionchannels that are essential for controlling neuronal excitability is potassium channel family and, hereby, the focus of thisreview is on the K+ channels in peripheral pain pathways. The aim of the review is threefold. First, we will discuss currentevidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we willconsider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathwaysis a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement ofK+ channels in nociceptive pathways as a strategy for new analgesic drug design.

Anoctamin 1 Mediates Thermal Pain as a Heat Sensor by Hawon Cho, Uhtaek Oh (641-651).
Vertebrates can sense and avoid noxious heat that evokes pain. Many thermoTRP channels are associated withtemperature sensation. TRPV1 is a representative ion channel that is activated by noxious heat. Anoctamin 1 (ANO1) is aCl- channel activated by calcium that is highly expressed in small sensory neurons, colocalized with markers fornociceptors, and most surprisingly, activated by noxious heat over 44°C. Although ANO1 is a Cl- channel, opening of thischannel leads to depolarization of sensory neurons, suggesting a role in nociception. Indeed, the functional deletion ofANO1 in sensory neurons triggers the reduction in thermal pain sensation. Thus, it seems clear that ANO1 is a heat sensorin a nociceptive pathway. Since ANO1 modulators are developed for the purpose of treating chronic diseases such ascystic fibrosis, this finding is likely to predict unwanted effects and provide a guide for better developmental strategy.

Targeting Pain-evoking Transient Receptor Potential Channels for the Treatment of Pain by Jialie Luo, Edgar T Walters, Susan M Carlton, Hongzhen Hu (652-663).
Chronic pain affects billions of lives globally and is a major public health problem in the United States.However, pain management is still a challenging task due to a lack of understanding of the fundamental mechanisms ofpain. In the past decades transient receptor potential (TRP) channels have been identified as molecular sensors of tissuedamage and inflammation. Activation/sensitization of TRP channels in peripheral nociceptors produces neurogenicinflammation and contributes to both somatic and visceral pain. Pharmacological and genetic studies have affirmed therole of TRP channels in multiple forms of inflammatory and neuropathic pain. Thus pain-evoking TRP channels emergeas promising therapeutic targets for a wide variety of pain and inflammatory conditions.

The efficacy of many of pain-relieving drugs is based on mechanisms by which the drugs interfere with thebody's natural pain-mediating pathways. By contrast, although it is less popular, other drugs including opioids exert morepowerful analgesic actions by augmenting endogenous inhibitory neural circuits for pain mediation. Recently, a novelendogenous pain-inhibitory principle was suggested and is now attracting both scientific and clinical attentions. Thecentral players for the actions are particular body lipids: resolvins. Although research is in the preclinical phase, multiplehypotheses have actively been matured regarding the potency and molecular and neural processes of the analgesic effectsof these substances. Consistently, accumulating experimental evidence has been demonstrating that treatment with theselipid substances is strongly effective at controlling diverse types of pain. Treatment of resolvins does not appear to disturbthe body homeostasis as severely as many other therapeutic agents that interrupt the body's natural signaling flow, whichenables us to predict their fewer adverse effects. This paper serves as a review of currently documented painkilling actionsof resolvins, summarizes the potential cellular and receptor-mediated mechanisms to date, and discusses the many clinicaluses for these therapeutic lipids that have not yet been tested. Future scientific efforts will more concentrate to unveil suchaspects of the substances and to construct clear proofs of concept for pain relief.