title: Independent contributions of alcohol and stress axis hormones to painful peripheral neuropathy.
abstract: Painful small-fiber peripheral neuropathy is a debilitating complication of chronic alcohol abuse. Evidence from previous studies suggests that neuroendocrine mechanisms, in combination with other, as yet unidentified actions of alcohol, are required to produce this neuropathic pain syndrome. In addition to neurotoxic effects of alcohol, in the setting of alcohol abuse neuroendocrine stress axes release glucocorticoids and catecholamines. Since receptors for these stress hormones are located on nociceptors, at which they can act to cause neuronal dysfunction, we tested the hypothesis that alcohol and stress hormones act on the nociceptor, independently, to produce neuropathic pain. We used a rat model, which allows the distinction of the effects of alcohol from those produced by neuroendocrine stress axis mediators. We now demonstrate that topical application of alcohol and exposure to unpredictable sound stress, each alone, has no effect on the nociceptive threshold. However, when animals that had previous exposure to alcohol were subsequently exposed to stress, they rapidly developed mechanical hyperalgesia. Conversely, sound stress followed by topical alcohol exposure also produced mechanical hyperalgesia. The contribution of stress hormones was prevented by spinal intrathecal administration of oligodeoxynucleotides antisense to β(2)-adrenergic or glucocorticoid receptor mRNA, which attenuates receptor level in nociceptors, as well as by adrenal medullectomy. These experiments establish an independent role of alcohol and stress hormones on the primary afferent nociceptor in the induction of painful peripheral neuropathy.
authors.affiliation: Departments of Medicine and Oral Surgery, Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0440, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Ferrari
authors.forename: E
authors.initials: E
authors.lastname: Levine
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D020269:Alcoholic Neuropathy / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005938:Glucocorticoids / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology / Q000523:psychology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
chemical_list: D002395:Catecholamines; D005938:Glucocorticoids; D000431:Ethanol