Depletion of Endogenous Noradrenaline Does Not Prevent Spinal Cord Plasticity Following Peripheral Nerve Injury

Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA.
The journal of pain: official journal of the American Pain Society (Impact Factor: 4.01). 12/2011; 13(1):49-57. DOI: 10.1016/j.jpain.2011.09.009
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The present study examined the role of endogenous noradrenaline on glial and neuronal plasticity in the spinal cord in rats after peripheral nerve injury. An intrathecal injection of dopamine-β-hydroxylase antibody conjugated to saporin (DβH-saporin) completely depleted noradrenergic axons in the spinal cord and also reduced noradrenergic neurons in the locus coeruleus (A6) and A5 noradrenergic nucleus in the brainstem and noradrenergic axons in the paraventricular nucleus of the hypothalamus. DβH-saporin treatment itself did not alter mechanical withdrawal threshold, but enhanced mechanical hypersensitivity and intrathecal clonidine analgesia after L5-L6 spinal nerve ligation. In the spinal dorsal horn of spinal nerve ligation rats, DβH-saporin treatment increased choline acetyltransferase immunoreactivity as well as immunoreactivity in microglia of ionized calcium binding adaptor molecule 1[IBA1] and in astrocytes of glial fibrillary acidic protein, and brain-derived nerve growth factor content. DβH-saporin treatment did not, however, alter the fractional release of acetylcholine from terminals by dexmedetomidine after nerve injury. These results suggest that endogenous tone of noradrenergic fibers is not necessary for the plasticity of α2-adrenoceptor analgesia and glial activation after nerve injury, but might play an inhibitory role on glial activation. PERSPECTIVE: This study demonstrates that endogenous noradrenaline modulates plasticity of glia and cholinergic neurons in the spinal cord after peripheral nerve injury and hence influences the pathophysiology of spinal cord changes associated with neuropathic pain.

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Available from: Christopher M Peters, Oct 08, 2015
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    • "Postsynaptic stimulation of ␣ 2 adrenoceptors at the level of the spinal cord increases acetylcholine concentrations in the superficial dorsal horn and inhibits nociceptive neurotransmission by reducing the release of neurotransmitters such as substance P and glutamate [20] [40] [46] [78]. Spinal alpha 2 -adrenoceptor stimulation produces analgesia in animals with neuropathic pain, and this effect in animals is blocked by inhibition of brain-derived neurotrophic factor (BDNF) signaling pathway [33] [34] [35]. Dexmedetomidine can also inhibit glial cell hypertrophy in the spinal dorsal horn and activation of the extracellular signal-regulated kinase (ERK) signaling pathway [18] [43]. "
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    ABSTRACT: Dexmedetomidine was initially approved for clinical use as a sedative. Its development in pain management has been limited. Dexmedetomidine has analgesic effects and analgesic-sparing properties, especially for patients with obstructed airways. Mixing dexmedetomidine with local anesthetics is a promising new avenue to enhance local anesthetics' effectiveness. Peripheral, spinal and supraspinal α2A-ARs are responsible for the analgesic function of dexmedetomidine. Animal studies have shown that antinociceptive synergism results from co-application of dexmedetomidine and opioids or local anesthetics. Dexmedetomidine has potential adverse effects such as hypotension and bradycardia. Therefore, dexmedetomidine is contraindicated for patients suffering from bradycardia or using β-adrenergic antagonists. Clinical trials of dexmedetomidine in chronic pain or hyperalgesia are lack.
    Neuroscience Letters 12/2013; 561. DOI:10.1016/j.neulet.2013.12.039 · 2.03 Impact Factor
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    • "In turn, this inhibits the release of excitatory neurotransmitters from primary nociceptive afferents and blocks pain. The effectiveness of this anti-nociceptive mechanism sometimes strengthens following peripheral nerve injury (Ma and Eisenach, 2003; Hayashida et al., 2012). However, under certain conditions, this spinal anti-nociceptive influence may be compromised after peripheral nerve injury (Rahman et al., 2008), thereby contributing to pain. "
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    Frontiers in Integrative Neuroscience 11/2012; 6:104. DOI:10.3389/fnint.2012.00104
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    ABSTRACT: Tissue and nerve damage can result in chronic pain. Yet, chronic pain after cesarean delivery is remarkably rare in women and hypersensitivity from peripheral nerve injury in rats resolves rapidly if the injury occurs in the puerperium. Little is known regarding the mechanisms of this protection except for a reliance on central nervous system oxytocin signaling. Here we show that the density of inhibitory noradrenergic fibers in the spinal cord is greater when nerve injury is performed in rats during the puerperium, whereas the expression of the excitatory regulators dynorphin A and neuregulin-1 in the spinal cord is reduced. The puerperium did not alter spinal cord microgial and astrocyte activation. Astrocyte activation, as measured by glial fibrillary acidic protein (GFAP) expression, was not evident in female rats with injury, regardless of delivery status suggesting sex differences in spinal astrocyte activation after injury. These results suggest a change in the descending inhibitory/facilitating balance on spinal nociception neurotransmission during the puerperium, as mechanisms for its protective effect against injury-induced hypersensitivity.
    Neuroscience 10/2012; 228:301–308. DOI:10.1016/j.neuroscience.2012.10.039 · 3.36 Impact Factor
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