An Introduction to Pain Pathways and Pain “Targets”

Vaskar Das1    Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA
1 Corresponding author: email address: vxd150530@utdallas.edu

1 An Introduction to Pain and Pain Pathways

The International Association for the Study of Pain (IASP) has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1 When asked to describe their pain, individuals variously described it in terms of severity (mild, moderate, severe), duration (acute or chronic), and type (nociceptive, inflammatory, neuropathic).2

Nociceptive pain is the normal acute pain sensation produced by activation of nociceptors in skin, viscera, and other internal organs in the absence of sensitization.3–7 It may occur as a result of mechanical, thermal, or chemical noxious stimulation and is variously described as an aching or throbbing kind of pain.5,6,8,9 Nociceptive pain comprises four main stages: transduction (i.e., action at receptors in the periphery), transmission (i.e., action potentials along axons), perception (i.e., cortical processing of nociceptive input), and modulation (i.e., engagement of descending circuits).4,10–12 Noxious stimuli are first detected by mechanical, thermal, and chemical nociceptors found on specialized nerve endings present in skin (cutaneous), viscera, and other internal or external organs.8,9,13,14 Nociceptive impulses are transmitted from the periphery to the spinal cord via primary afferent nerve fibers which may be unmyelinated or myelinated.3,15–20 The central nervous system (CNS) components of this pathway constitute particular anatomical connections in the spinal cord, brain stem, thalamus, and cortex (the “pain pathway”), linking the sensory inflow generated in high threshold primary afferents with those parts of the CNS responsible for conscious awareness of painful sensations21 (Fig. 1). Unmyelinated nerve fibers are small diameter C-fibers with diameters in the range 0.4–1.2 μm.22,23 Myelinated primary afferent nerve fibers are the Að-fibers (2–6 μm diameter), whereas the thinly myelinated nerve fibers are the Aβ-fibers (> 10 μm diameter).23,24 Primary afferent C-fibers and Að-fibers are responsible for transmission of noxious stimuli whereas Aβ-fibers transmit innocuous, mechanical stimuli such as touch.21–24 Put simply, nociceptors collect information from noxious stimuli which are transmitted by C-fibers and Að-fibers through the dorsal root ganglia to the superficial laminae I/II of the dorsal horn of the spinal cord.20,23 Að-fibers transmit impulses from the dorsal horn to deeper laminae (III–IV) of the spinal cord and onto higher centers in the brain via the spinothalamic tracts.20 Dorsal horn neurons comprise (i) projection neurons, (ii) local interneurons, and (iii) propriospinal neurons.20,25 Although projection neurons are the primary means for transferring sensory information from the spinal cord to the brain, they are only a small fraction of the total number of cells in the dorsal horn.23,26 Many projection neurons have axons that cross the midline and ascend to multiple areas of the brain including the thalamus, periaqueductal gray matter, lateral parabrachial area of the pons, and various parts of the medullary reticular formation.27 These neurons are also involved in activation of endogenous descending inhibitory pathways that modulate dorsal horn neurons.26 Activity-dependent synaptic plasticity in the spinal cord that generates postinjury pain hypersensitivity together with the cellular and molecular mechanisms responsible for this form of neuronal plasticity are termed “central sensitization.”21 Neuroplastic changes relating to the function, chemical profile, or structure of the peripheral nervous system are encompassed by the term “peripheral sensitization” and encompass changes in receptor, ion-channel, and neurotransmitter expression levels.28,29 Central sensitization in the spinal cord includes sensitization and disinhibition mechanisms, and supraspinally there are functional changes such as enlargement of receptive fields.30,31 In the CNS, there are also changes in the dynamic interplay between neuronal structures and activated glial cells,30,32,33 a topic covered in depth in Chapter “Nonneuronal Central Mechanisms of Pain: Glia and Immune Response” by E. Alfonso Romero-Sandoval and Sarah Sweitzer.

Following tissue injury and inflammation, vasoactive mediators such as histamine, substance P (SP), serotonin (5-HT), nitric oxide (NO), prostaglandins (PGs), and bradykinin are released which activate nociceptors resulting in nociception.13 This in turn can induce release of pronociceptive neurotransmitters such as SP, calcitonin gene-related peptide (CGRP), dynorphin (Dyn), neurokinin A (NKA), glutamate, adenosine triphosphate (ATP), NO, PGs, and neurotrophins such as brain-derived neurotropic factor (BDNF), from primary afferents either in the periphery or at the first synapse in the dorsal horn of the spinal cord.13,20,22,34,35 More recently, the important role of proinflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-1β, interleukin-18, etc.) in peripheral and central sensitization mechanisms associated with persistent pain states has begun to be appreciated.36

Many C-fibers express transient receptor potential vanilloid 1 (TRPV1) receptors and hence are sensitive to the vanilloid, capsaicin, which is a high-affinity ligand for TRPV1 receptors.37 TRPV1-expressing C-fibers may be further subdivided into two major classes:

(i) those that contain the neuropeptides, SP, and CGRP, express the high-affinity nerve growth factor (NGF) receptor, TrkA, and are developmentally dependent on NGF,34,38,39 and

(ii) those that express isolectin B4, (IB-4), the P2X3 purinergic receptor,40 fluoride-resistant acid phosphatase, do not contain SP or CGRP,41 and are dependent on glial cell line-derived neurotrophic factor (GDNF).34

1.1 Neuropathic pain

The IASP has defined neuropathic pain as “Pain initiated or caused by a primary lesion or dysfunction in the nervous system.”1,42 Neuropathic pain is variously described by patients as having one or more of the following qualities: burning, tingling, electric shock like, and stabbing or pins and needles.5,42,43 The appearance of abnormal sensory signs such as allodynia in response to innocuous (nonnoxious) stimulation and/or hyperalgesia in response to noxious stimulation is common.43 When neuropathic pain is evoked, it may be classified as having dysesthetic, hyperalgesic, or allodynic properties depending upon the dynamic or static characteristics of the stimulus.44

In recent years, it has begun to be appreciated that the pathobiology of various neuropathic pain subtypes may differ.45,46 Hence, multiple research groups have focussed on developing and validating rodent models of each of these neuropathic pain conditions.47,48 These more relevant rodent models of neuropathic pain have considerable potential not only in terms of unraveling the neurobiology of each...