Mechanical stimuli are sensed and translated into electrical and biochemical signals by mechanosensitive neurons. Sensory information is transmitted from the peripheral nervous system to the central nervous system via primary afferents. Primary afferents project axons distally to innervate peripheral targets and centrally to the spinal cord (O’Brien et al. 1989; Steeds 2009; Dubin and Patapoutian 2010). Their cell bodies are contained in the DRG (Figure 1.3); afferent axons extending from the DRG to the spinal cord form the dorsal nerve root and synapse with neurons in the spinal dorsal horn (Figure 1.3) (Markenson 1996).
The spinal cord is organized into laminae consisting of ten layers of grey matter (I-X) (Rexed 1952; Molander et al. 1989). Laminae in the spinal dorsal horn contain second-order neurons that receive input from specific populations of primary afferents (Todd 2010). C and Aδ nociceptors synapse mostly with projection neurons and interneurons in the superficial dorsal horn (laminae I-II), with some Aδ fibers connecting more deeply in lamina V (Basbaum et al. 2009; Todd 2010) (Figure 1.3). In contrast, the myelinated A fibers, which are tactile and hair afferents carrying innocuous inputs, terminate mainly in the deep laminae (III-V), with some extension into the ventral half of the inner lamina II (Figure 1.3) (Basbaum et al. 2009; Todd 2010).
There are three main classes of neurons in the spinal cord that receive input from the primary afferents. Second-order neurons are classified as nociceptive specific (NS), low-threshold mechanoreceptive (LTM), or wide dynamic range (WDR), based on their evoked responses to stimulations (Saito et al. 2008; Quinn et al. 2010b). NS neurons in
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Figure 1.3. Neuroanatomy of the dorsal root ganglion (DRG) and the spinal cord. Primary afferents, with their cell bodies in the DRG, transmit sensory information from the periphery to the spinal cord. Afferents terminate in different spinal dorsal horn laminae. The superficial laminae (I-II) receive input mainly from nociceptive C and A fibers; most of the tactile sensory A fibers and some of the A nociceptors synapse in the deep laminae (III-V).
the superficial laminae synapse with C and A nociceptors and are only activated by noxious stimuli (Woolf and Fitzgerald 1983; Saito et al. 2008; Steeds 2009). The deep laminae contain both LTM neurons that respond maximally to light innocuous stimuli and WDR neurons that exhibit a graded response to innocuous and noxious stimuli (Saito et al. 2008; Steeds 2009). Both LTM and WDR neurons receive input from Aδ nociceptors and Aβ light-touch receptors (Woolf and Fitzgerald 1983; Saito et al. 2008; Steeds 2009; Basbaum et al. 2009).
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From the spinal dorsal horn, sensory information is conveyed by spinal projection neurons along ascending pathways to higher order structures in the brain (Julius and Basbaum 2001; Steeds 2009). A large number of projection neurons reside in lamina I; a majority of them express the neurokinin 1 (NK1) receptor for substance P that is released by peptidergic C nociceptors (Todd 2002; D’Mello and Dickenson 2008). Those NK1- positive projection neurons transmit nociceptive signals to several brain regions including the parabrachial area and periaqueductal grey (Todd 2002). In addition, they innervate the brainstem and activate descending pathways that modulate spinal processing (Mantyh et al. 1997; Suzuki et al. 2002; D’Mello and Dickenson 2008). Projection neurons in the deep laminae project predominantly to the thalamus, a brain area that relays pain signals to the cerebral cortex for further processing and sensation (D’Mello and Dickenson 2008; Steeds 2009; Yen and Lu 2013).
The generation of pain normally serves as a protective mechanism that signals to the brain of existing or potential tissue injury (Woolf and Salter 2000a; Steeds 2009). Nociception can provide feedback to promote tissue adaptation and/or repair (Woolf and Salter 2000a; Steeds 2009). However, potentiation of nociceptive processing can develop into a chronic neurological disorder, deviating from the protective properties of pain (Dubner and Ruda 1992; Coderre et al. 1993). Aberrant activation of nociceptors can result in sensitization that involves pathologic neuronal responses in the central nervous system, leading to pain (Lee et al. 2004b; Latremoliere and Woolf 2009; Dubin and Patapoutian 2010; Gold and Gebhart 2010; Zhang et al. 2013). Noxious stimuli commonly induce decreased response thresholds to thermal and mechanical stimuli in the
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regions that are supplied by the affected nerves; those regions are referred to as dermatomes. For instance, the C6 and C7 dermatomes include several anatomical regions that are innervated by the C6 and C7 spinal nerves, like the arms, shoulders, and bilateral C6/C7 facet joints (Dwyer et al. 1990; Hauser et al. 2015). Because of this widespread innervation pattern and the fact that the C6/C7 facet joints are commonly involved in neck trauma from whiplash (Panjabi et al. 1998b; Pearson et al. 2004), whiplash patients routinely report pain and sensitivity in the upper arm and shoulder area (Dwyer et al. 1990; Barnsley et al. 1994; Kasch et al. 2001).
Nociceptors can be activated at their peripheral terminals by external stimuli, such as heat and mechanical loading (Khalsa et al. 1997; Julius and Basbaum 2001; Chen et al. 2006). Noxious stimuli alter the electrophysiological properties of the afferents, which includes lowering their thresholds for firing, increasing their firing rates, and inducing their persistent activation (Cavanaugh et al. 2006; Costigan et al. 2009; Nicholson et al. 2011). In addition, tissue damage can up-regulate the release of inflammatory mediators from the nociceptor, as well as the expression of receptors to inflammatory molecules, like cytokines and neurotrophins (Basbaum et al. 2009; Kras et al. 2013a; Kras et al. 2013c; Kras et al. 2015a). Nociceptive signals are transmitted to the spinal cord via the release of neurotransmitters, such as glutamate and the neuropeptides substance P and CGRP, from the primary afferents (Julius and Basbaum 2001; Basbaum et al. 2009). Together, these nociceptor responses can lead to increased excitability of spinal neurons and their transmission of nociceptive information to the brain (Julius and Basbaum 2001; Costigan et al. 2009; Latremoliere and Woolf 2009). Numerous other complex cellular
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mechanisms, such as neuron-glia interactions and glutamatergic neurotransmission, are involved in the generation of a prolonged hyperexcitability state in the central nervous system, a state referred to as central sensitization (Basbaum et al. 2009). Central sensitization manifests as mechanical hyperalgesia and is associated with the development of chronic pain.