Autonomía en el marco de relaciones

Whiplash injuries can produce a variety of symptoms that are collectively termed “whiplash-associated disorders” (Jansen et al., 2008; Spitzer et al., 1995). The symptoms of whiplash-associated disorders may include neck and back pain, dizziness, tinnitus, headache, paresthesias, temporomandibular joint pain, and disturbances in concentration, vision, or memory (Barnsley et al., 1995; Jansen et al., 2008; Lord et al., 1996). Patients with whiplash-associated disorders demonstrate painful responses to stimuli that are normally non-noxious (allodynia), increased sensitivity to noxious stimuli (hyperalgesia), and local and widespread decreases in the activation thresholds of spinal reflexes (Banic et al., 2004; Curatolo et al., 2001; Moog et al., 2002; Sheather-Reid and Cohen, 1998;

Van Oosterwijck et al., 2013). The body is divided into dermatomes that correspond to

the regions that are innervated by each spinal level (Fig. 1.6). Whiplash-associated pain symptoms often develop in a dermatome-specific fashion, depending on the spinal level of the symptomatic facet joints (Dwyer et al., 1990). For example, the C6 and C7 levels of the spinal cord receive primary afferent innervation from the arms, shoulders, and back, including the C6/C7 facet joints (Fig. 1.6). Those anatomical regions, collectively called the C6 and C7 dermatomes, commonly develop decreased pain thresholds after noxious stimulation of C6/C7 facet joint (Aprill, 1990; Dwyer et al., 1990).

The cervical spine anatomy, neurophysiology, and dermatomal distribution of the rat are similar to those of the human (Fig. 1.6), enabling the use of rat models to investigate the biomechanical and neurophysiological mechanisms underlying persistent pain. A rat model of facet joint loading has been developed to evaluate the development of persistent facet-mediated pain. Facet joint loading is induced in rats by distracting the facet joint to induce capsule stretch and simulate the injurious tensile strains that occur in the capsule during whiplash (Dong et al., 2012; Lee et al., 2004a; Lee et al., 2008; Pearson et al., 2004; Siegmund et al., 2001). Behavioral sensitivity develops one day after injurious C6/C7 facet joint loading and persists for up to six weeks (Rothman et al., 2008). Pain develops in the shoulders, neck, and forepaws in a dermatome-specific pattern similar to the symptoms that develop following noxious stimulation of the human cervical facet capsule (Fig. 1.6) (Crosby et al., 2014a; Curatolo et al., 2001; Dong et al.,

Fig. 1.6. Patterns of sensory innervation in the cervical region of the human and rat.

Pain commonly develops in the C6 and C7 dermatomes after noxious stimulation or

loading of the C6/C7 facet joints. (a) The C6/C7 dermatomes are highlighted on a

human dermatomal map. (b) Corresponding innervation patterns and locations of

behavioral hypersensitivity after painful C6/C7 facet joint injury are shown for the rat (adapted from Takahashi and Nakajima, 1996).

C6/C7 Dermatomes

b)

a)

2012; Dwyer et al., 1990; Lee et al., 2008; Van Oosterwijck et al., 2013). However, physiologic strains in the facet capsule do not induce behavioral sensitivity in the rat, and capsule transection that alleviates mechanical loading of the capsule prevents the development sensitivity (Dong et al., 2012; Lee and Winkelstein, 2009; Winkelstein and Santos, 2008). Together, these findings suggest that capsule strain magnitude plays a key role in the initiation of persistent facet joint pain.

Injurious C6/C7 facet joint loading that produces pain in rats induces spinal modifications that are associated with central sensitization. Neurons in the dorsal horn of the spinal cord develop hyperexcitability by day 7 after painful facet joint injury (Dong et al., 2013a; Quinn et al., 2010b), including increased responses of WDR neurons to both non-noxious and noxious mechanical stimulation of the forepaw (Quinn et al., 2010b). Intrathecal treatment with gabapentin, a neuropathic pain drug that reduces neuronal excitability, attenuates spinal hyperexcitability and behavioral sensitivity (Dong et al., 2013a), further supporting that neuronal sensitization contributes to persistent facet- mediated pain.

Spinal hyperexcitability may be facilitated by increases in excitatory glutamatergic signaling in the dorsal horn after painful facet joint injury. Metabotropic glutamate receptor mGluR5 is upregulated in the dorsal horn seven days after painful facet injury, while neuronal glutamate transporter EAAC1 expression is decreased at that time point (Dong and Winkelstein, 2010). Increases in mGluR5 and decreases in EAAC1 correlate to the magnitude of capsule strain, suggesting that mechanotransduction of facet capsule loading alters spinal glutamatergic signaling (Dong and Winkelstein, 2010). Painful facet joint injury also increases spinal expression of PKCε (Dong et al., 2012), a

member of one kinase family that contributes to neuronal hyperexcitability in central sensitization (Chen and Huang, 1992; Kawasaki et al., 2004). Although some components of glutamate signaling have been characterized after painful facet joint injury, many glutamate signaling proteins that play important roles in central sensitization have not been studied after facet joint injury, including the activation of NMDA receptors and the expression of astrocytic glutamate transporters GLAST and GLT1.

Spinal glial activation also develops after painful facet joint injury in the rat, as measured by an increase in GFAP expression in spinal astrocytes at day 7 after injury (Lee et al., 2004a; Weisshaar et al., 2010). Astrocyte activation has been reported to be modulated by the magnitude of facet capsule stretch, because GFAP expression exhibits a graded response to sham procedures, physiologic or injurious levels of facet capsule stretch, and joint distraction that causes rupture of the capsule (Lee et al., 2004a; Lee et al., 2008). Intrathecal gabapentin treatment that reduces spinal hyperexcitability also attenuates the injury-induced increase in GFAP in the dorsal horn (Dong et al., 2013a), suggesting that GFAP expression is modulated by spinal neuronal activity. However, the relationship between mechanical facet joint injury and the spinal neuronal and glial activation that may contribute to persistent pain has not been fully defined.