Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain.
Chronic pain after peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)-related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5 to L6 spinal nerve ligation (SNL) in rats increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal but not SNL animals. Accordingly, gabapentin increased c-fos expression in LC neurons and noradrenaline release in the PFC in normal animals, but in SNL animals, gabapentin failed to increase c-fos expression in LC neurons projecting to the PFC and failed to increase noradrenaline release in the PFC. In contrast, locally perfused gabapentin reduced noradrenaline release in the PFC in vivo and in PFC synaptosomes in vitro. SNL- and gabapentin-induced impairment of novel object recognition task were reversed by intraperitoneal injection of the α1-adrenoceptor antagonist prazosin. These results suggest that increase in noradrenergic tone, induced by nerve injury or gabapentin, impairs PFC functions possibly via α1-adrenoceptor-mediated mechanisms; that the net effect of gabapentin on noradrenaline release in the PFC would depend on sometimes opposing actions at different sites; and that nerve injury selectively impairs the response to gabapentin in PFC-projecting neurons in the LC.
Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Takashi
T
Suto
Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
James C
JC
Eisenach
Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: khayashi@wakehealth.edu.
Ken-Ichiro
K
Hayashida
D059331:Adrenergic Neurons / Q000187:drug effects* / Q000378:metabolism; D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D059350:Chronic Pain / Q000209:etiology / Q000378:metabolism / Q000523:psychology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D000077206:Gabapentin; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism / Q000523:psychology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D016760:Proto-Oncogene Proteins c-fos; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009638:Norepinephrine
Chronic pain; Locus coeruleus; Noradrenaline; Novel object recognition task; Prefrontal cortex; Spinal nerve ligation