Intact cutaneous C fibre afferent properties in mechanical and cold neuropathic allodynia

Abstract

Patients with neuropathy, report changes in sensory perception, particularly mechanical and thermal allodynia, and spontaneous pain. Similar sensory changes are seen in experimental neuropathies, in which alteration in primary afferent properties can also be determined. The neural correlate of spontaneous pain is ongoing activity in sensory afferents. Mechanical and heat allodynia are thought to result from lowered activation thresholds in primary afferent and/or central neurones, but the mechanisms underlying cold allodynia are very poorly understood.We investigated nociceptive behaviours and the properties of C and A fibre intact afferents running adjacent to damaged afferents following a partial ligation injury of the saphenous nerve (PSNI). Animals developed mechanical and cold allodynia by 3 days after PSNI. Intact mechanosensitive C fibre afferents developed ongoing activity, and had slower conduction velocities 3 and 7 days following nerve injury, with no change in mechanical threshold. There was a large increase (∼46-fold) in calculated afferent input 3 days after nerve injury, as a result of the ongoing activity in these fibres. Mechano-cooling-sensitive C fibre afferents showed both enhanced cooling-evoked firing, and increased ongoing activity. The afferent barrage associated with mechano-cooling-sensitive afferents was increased 26-fold 7 days after nerve injury. We observed no differences in the properties of intact A fibre mechanosensitive afferents.These studies demonstrate for the first time that the altered nociception seen after PSNI is associated with ongoing activity and enhanced cooling-evoked activity in intact C fibre afferents in the saphenous nerve, with no concurrent alteration in A fibre afferents.

Spinal Processing of Noxious and Innocuous Cold Information: Differential Modulation by the Periaqueductal Gray

“…Acetone produced only mild cooling of the skin and never evoked withdrawal reflexes in lightly anesthetized rats, consistent with observations that normal rats show little or no response to acetone, and with the use of acetone as a test for cold allodynia following neuropathy (Choi et al, 1994;Decosterd and Woolf, 2000;Kim et al, 2009;Hulse et al, 2010). Together with reports from human studies that temperatures between 15 and 20°C are perceived as cool (Greenspan et al, 1993), this suggests that acetone produces predominantly innocuous cooling.…”

“…Nonetheless, it is likely that the temperature changes produced by acetone application will activate a small proportion of nociceptive afferents, since some cold-responsive nociceptors are reported to have activation thresholds of Ͼ20°C (although most have thresholds at much colder temperatures) Campero et al, 1996;Simone and Kajander, 1996). Clearly, however, activation of such afferents is not generally sufficient to produce overt behavioral responses to acetone, either in lightly anesthetized rats (this study) or in awake normal rats, which show little or no response to acetone (Choi et al, 1994;Decosterd and Woolf, 2000;Kim et al, 2009;Hulse et al, 2010); therefore, we consider acetone to be predominantly (though not exclusively) an innocuous cooling stimulus.…”

Comparison of operant escape and reflex tests of nociceptive sensitivity

“…The selective enhancement of cold sensitivity by CCI is reinforced by thermal preference testing (10 • C vs. 45 • C), which reveals enhanced cold aversion over 14 weeks following bilateral CCI. Human evidence for cold allodynia/hyperalgesia but not heat allodynia/hyperalgesia is substantial (Hulse et al, 2010;Jorum et al, 2003;Landerholm et al, 2010;Argyriou et al, 2007;Davis et al, 1991;Frost et al, 1988;Price et al, 1989;Wahren et al, 1991). CCI appears to model sympathetically maintained pain (SMP) (Grelik et al, 2005), which results from mild nerve injury (Wahren et al, 1991).…”

“…Reflex testing of laterally hemisected animals has described a pattern of increased sensitivity for stimulation of each hindpaw (and inexplicably, both forepaws) (Christensen et al, 1996;Hulsebosch et al, 2009). In addition to involvement of the spinothalamic pathway, descending inhibitory pathways are interrupted by hemisection (Kwon et al, 2013), which could change the results compared to an anterolateral lesion.…”

“…(2) Sensitivities to painful stimulation can characterize most clinical pain conditions in ways that meaningfully elaborate on reports of the presence and intensity or quality of ongoing pain. For example, neuropathic pain from nerve injury is characterized by a high sensitivity to tactile stroking and cold stimulation but not to heat stimulation (Hulse et al, 2010;Jorum et al, 2003;Landerholm et al, 2010;Price, 1989). Tests for numerous psychophysical attributes can be adapted and applied to animal models of different pain conditions if operant techniques are utilized.…”