Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia

Abstract

In humans, trauma to a peripheral nerve may be followed by chronic pain syndromes which are only relieved by blockade of the effects of sympathetic impulse traffic. It is presumed that, after the lesion, noradrenaline released by activity of sympathetic postganglionic axons excites primary afferent neurons by activating alpha-adrenoceptors, generating signals that enter the 'pain pathways' of the central nervous system. The site of coupling is unclear. In some patients local anaesthesia of the relevant peripheral nerve does not alleviate pain, implying that ectopic impulses arise either within the central nervous system, or in proximal parts of the primary afferent neurons. In experimentally lesioned rats, activity can originate within the dorsal root ganglia. Here we report that, after sciatic nerve ligation, noradrenergic perivascular axons in rats sprout into dorsal root ganglia and form basket-like structures around large-diameter axotomized sensory neurons; sympathetic stimulation can activate such neurons repetitively. These unusual connections provide a possible origin for abnormal discharge following peripheral nerve damage. Further, in contrast to the sprouting of intact nerve terminals into nearby denervated effector tissues in skin, muscle, sympathetic ganglia and sweat glands, the axons sprout into a target which has not been partially denervated.

Inflammation in CRPS: Role of the sympathetic supply

“…In animal models of peripheral nerve lesions, sympathetic nerve sprouting was also detected in the dorsal root ganglia (DRG) and these sympathetic fibers formed baskets around large primary neuronal cell bodies (Gibbs et al 2008;McLachlan et al, 1993;Pertovaara, 2006), of non-nociceptive A-fibers (Michaelis et al, 1996). In cultured DRG neurons, α 1 -adrenoceptor stimulation increases cell excitability, whereas β-adrenergic stimulation reduces it (Pluteanu et al, 2002).…”

Neuropathic pain: Early spontaneous afferent activity is the trigger

“…Modifications are observed at several anatomical locations after peripheral nerve injury, including: (1) a large increase in spontaneous (ectopic) activity in dorsal root ganglia (DRG) cell bodies and injured afferent fibers (Wall and Gutnick, 1974); (2) abnormal contacts between sympathetic and sensory nervous systems (McLachlan et al, 1993); and (3) changes in the spinal cord and brain. Although much is known about what molecular and cellular changes occur at these sites in neuropathic pain, including changes in gene expression (Xiao et al, 2002), it is not clear what event(s) and which anatomical site(s) are critical in initially triggering development of neuropathic pain.…”

α2-Adrenoceptor Stimulation Transforms Immune Responses in Neuritis and Blocks Neuritis-Induced Pain

“…Sympathetic nervous system activity likely exacerbates some neuropathic pain states (Koltzenburg and McMahon, 1991), considered to reflect novel expression of excitatory ␣-adrenoceptors on nociceptors (Sato and Perl, 1991) and sprouting of sympathetic fibers to surround sensory afferent terminals and cell bodies (McLachlan et al, 1993). Sympathetic nervous system effects on immune cells in pain states have been mostly ignored, although many classes of leukocytes express adrenoceptors (Josefsson et al, 1996) and leukocyte responses to challenge can be modulated by increasing sympathetic nervous system activity or by exogenous adrenoceptor agonists (Moynihan et al, 2004).…”