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Pain Research Product Guide | Edition 2 Pain Research Product Guide | Edition 2 Chili plant Capsicum annuum A source of Capsaicin Contents by Research Area: • Nociception • Ion Channels • G-Protein-Coupled Receptors • Intracellular Signaling Tocris Product Guide Series Pain Research Contents Page Nociception 3 Ion Channels 4 G-Protein-Coupled Receptors 12 Intracellular Signaling 18 List of Acronyms 21 Related Literature 22 Pain Research Products 23 Further Reading 34 Introduction Pain is a major public health problem with studies suggesting one fifth of the general population in both the USA and Europe are affected by long term pain. The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Management of chronic pain in the clinic has seen only limited progress in recent decades. Treatment of pain has been reliant on, and is still dominated by two classical medications: opioids and non-steroidal anti-inflammatory drugs (NSAIDs). However, side effects such as dependence associated with opioids and gastric ulceration associated with NSAIDs demonstrates the need for new drug targets and novel compounds that will bring in a new era of pain therapeutics. Pain has been classified into three major types: nociceptive pain, inflammatory pain and neuropathic or pathological pain. Nociceptive pain involves the transduction of painful stimuli by peripheral sensory nerve fibers called nociceptors. Neuropathic pain results from damage or disease affecting the sensory system, and inflammatory pain represents the immunological response to injury through inflammatory mediators that contribute to pain. Our latest pain research guide focuses on nociception and the transduction of pain to the spinal cord, examining some of the main classical targets as well as emerging pain targets. It is hoped that a thorough understanding of nociceptive pain will lead to the identification of key interventions most likely to provide therapeutic benefit in the future. Tocris Bioscience provides a range of high performance life science reagents that enable researchers to target the mechanisms that underlie pain. A selection of our key products are highlighted within each section, and a full product listing can be found on pages 23-33. Key Pain Research Products Box Number Title Page Box Number Title Page Box 1 TRP Channel Products 5 Box 8 Cannabinoid Receptor Products 12 Box 2 Sodium Channel Products 6 Box 9 Cannabinoid Modulation Products 14 Box 3 Calcium Channel Products 8 Box 10 Opioid Receptor Products 16 Box 4 Potassium Channel Products 9 Box 11 mGlu and GABAB Receptor Products 16 Box 5 iGlu and GABAA Receptor Products 9 Box 12 Bradykinin and Tachykinin Receptor Products 17 Box 6 P2X Receptor Products 10 Box 13 Intracellular Signaling Products 19 Box 7 Nicotinic Receptor Products 11 2 | PAIN RESEARCH Nociception Nociception is a process involving transduction of intense ther- of sensory neurons and whether or not they are myelinated. mal, chemical or mechanical stimuli that is detected by a sub- Most nociceptors are unmyelinated C-fibers that contribute population of peripheral nerve fibers called nociceptors (also to a poorly-localized sensation of secondary pain, whilst called pain receptors). Whilst neuropathic pain results from fast-onset, sharp pain is mediated by myelinated A-fibers. damage or disease affecting the sensory system, nociceptive The cell bodies of nociceptive neurons in the dorsal root gan- pain is the normal response to noxious insult or injury of tissues glion (DRG) send two processes: one axon to the peripheral including: skin, muscle, organs, joints, tendons and bones. tissue, and a second axon that synapses on second order neu- Inflammatory pain, while not discussed in this guide, is charac- rons in the dorsal horn of the spinal cord. The central axon of terized by the mobilization of white blood cells and anti bodies, DRG neurons enters the spinal cord via the dorsal root and leading to swelling and fluid accumulation. Noxious signals branches to innervate multiple spinal segments in the rostral can be enhanced or sensitized by inflammatory mediators, and caudal direction (laminae I, II, IIA and V), from which the during which pain fibers are activated by this lower intensity ascending nociceptive pathways originate (Figure 1). Within stimuli, and the pain generated can be more persistent. NSAIDs these laminae, DRG neurons may interact with both excitatory (such as aspirin (Cat. No. 4092), ibuprofen (Cat. No. 2796) and and inhibitory interneurons that help to fine-tune the incoming valdecoxib (Cat. No. 4206)) which inhibit cyclooxygenases, are signals. Calcium channels play a key role in the transmission of one of the most popular drug types used to prevent inflamma- the pain signal, by triggering release of neuropeptides such as tory pain in humans, but are not without severe side effects, substance P, neurokinin 1 and calcitonin gene-related peptide highlighting the need for new pain targets. (CGRP), as well as neurotransmitters such as glutamate. The Nociceptors are activated by noxious stimuli such as tis- ascending relay neurons then project to the medulla, mesen- sue injury, exposure to an acid or irritant, or extreme tem- cephalon and thalamus in the brain, which in turn project to peratures. They generate electrophysiological activity that is the somatosensory and anterior cingulate cortices to drive the transmitted to the spinal cord. Nociceptors can be divided cognitive aspects of pain. Both local GABA-releasing inhibitory functionally into three compartments: the peripheral terminal interneurons in the dorsal horn and descending noradrenergic which detects painful stimuli; the axon which transduces the neurons originating in the brain can inhibit pain signaling. signal; and the presynaptic terminal which transmits the sig- Signals relayed from nociceptors may act in combination to nal, using glutamate as a primary neurotransmitter, across the produce changes that lead to hyperalgesia: an over-exaggerated synapse to second order neurons. There are two major classes response to normally painful mechanical or thermal stimuli, of nociceptor: myelinated A-fibers and unmyelinated C-fibers. or allodynia: a pain from a stimulus that would not normally The speed of transmission is correlated to the axon diameter provoke pain. Figure 1 | Nociceptive pain pathway To brain From brain Ascending nociceptive pathway Descending inhibitory pathway • Glutamate • Neurokinin-1 • GABA • Opioids • Substance P • CGRP • Noradrenalin • Serotonin Dorsal horn Dorsal root ganglion (DRG) i Unmyelinated C-fibers ii iii iv v Peripheral vi tissues: Nociceptors skin, muscle, organs, joints, Spinal cord segments tendons or Spinal cord bones Myelinated A-fibers The cell bodies of nociceptors are located in the dorsal root ganglion (DRG) and terminate as free endings in peripheral tissues. Pain signals originating from the periphery pass through the dorsal root ganglion carried by C-fiber nerves (red) and myelinated A-fiber nerves (blue). Inputs directed to the dorsal horn synapse on interneurons that modulate the transmission of nociceptive signals to higher CNS centres. Signals are relayed to the brain via ascending pathways, and descending pathways from the brain send inhibitory signals. Highlighted in the boxes are key mediators and drug targets that play important roles in pain processing and transmission. www.tocris.com | 3 Tocris Product Guide Series Ion Channels signals encode the intensity of a noxious stimulus, leading to the Products by Category Page transduction of pain signals (Figure 2). Recently, TRP (transient receptor potential) channels have been pursued as pain targets ASIC Channels ...........................................................................................23 since they were identified at the genetic level and found to medi- Calcium Channels ...................................................................................23 ate the painful effects of capsaicin (via the TRPV1 channel), the GABA Receptors ....................................................................................25 A chemical responsible for the pungency of chili. A more classical Glutamate (Ionotropic) Receptors ................................................26 understanding of the ion channels involved in pain implicates HCN Channels ...........................................................................................27 the sodium channels, these determine excitability of the neurons Nicotinic Receptors ................................................................................28 alongside the calcium channels that influence membrane poten- Potassium Channels ..............................................................................30 tial and neuro transmission. Potassium channels are important Purinergic P2X Receptors ................................................................... 31 in repolar izing neurons back to a resting state, and could be Sodium Channels .................................................................................... 31 important targets in the future, alongside the emerging roles TRP Channels .............................................................................................32 that the ASIC, HCN and P2X receptor ion channels play in pain. Nociceptors express a wide variety of voltage-gated and ligand- TRP Channels gated ion channels that transduce receptor potential
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