title: Diabetic neuropathic pain: a role for testosterone metabolites.
abstract: Diabetic neuropathy is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. In this study, we analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT), and 3α-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of the spinal cord and in the dorsal root ganglia of rats rendered diabetic by streptozotocin injection. Furthermore, the levels of DHT and 3α-diol were analyzed in the spinal cord. Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3α-diol treatments. In addition, 3α-diol treatment resulted in a significant increase in 3α-diol in the spinal cord compared with control values. Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action. Indeed, DHT counteracted the effect of diabetes on the mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity, and expression of interleukin-1β (IL1β), while 3α-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, IL1β, and translocator protein. These results indicate that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.
authors.affiliation: Section of Biomedicine and Endocrinology, Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy Neuromuscular Disease Unit, IRCCS 'Carlo Besta' Neurological Institute, Milan, Italy Department of Pharmacy and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy Instituto Cajal, C.S.I.C., Madrid, Spain.
authors.forename: Donato
authors.initials: D
authors.lastname: Calabrese
authors.forename: Silvia
authors.initials: S
authors.lastname: Giatti
authors.forename: Simone
authors.initials: S
authors.lastname: Romano
authors.forename: Carla
authors.initials: C
authors.lastname: Porretta-Serapiglia
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianchi
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Barbara
authors.initials: B
authors.lastname: Viviani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Garcia-Segura
authors.forename: Roberto Cosimo
authors.initials: RC
authors.lastname: Melcangi
mesh_terms: D000818:Animals; D003929:Diabetic Neuropathies / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D059226:Nociceptive Pain / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*
chemical_list: D013196:Dihydrotestosterone; D015847:Interleukin-4; D013739:Testosterone
keywords: astrocyte immunoreactivity; cytokines; diabetic neuropathy; glutamate; neuroactive steroids; streptozotocin; substance P; synaptic proteins