Alpha 1 adrenoceptor expression in skin, nerves and blood vessels of patients with painful diabetic neuropathy.

Diabetic neuropathy (dNP) patients often suffer from severe neuropathic pain. It was suggested that alpha-1 adrenoceptor (α-AR) hyperresponsiveness contributes to pain in dNP. The aim of our study was to quantify α-AR expression using immunohistochemistry in skin biopsies of nine patients with painful diabetic neuropathy compared to 10 healthy controls. Additionally, the association between α-AR expression and activation with spontaneous and sympathetically maintained pain (SMP) induced by intradermal injection of the α-agonist phenylephrine was investigated. For control purposes the α-agonist clonidine was injected in a different session. We found that dermal nerve density was significantly lower in dNP than in controls. However, α-AR expression was significantly greater on cutaneous blood vessels and keratinocytes of dNP patients than controls. A similar trend, which failed to reach significance, was observed for dermal nerves. Intradermal injection of phenylephrine induced only minor pain, which resolved after a few minutes. Adrenergically evoked pain persisted for more than 15 min in only one patient, but none of the patients fulfilled the criteria for SMP (pain increase after injection of phenylephrine and decrease after clonidine). In conclusion, our results imply that SMP does not occur in dNP. However, elevated expression of α-AR on keratinocytes and dermal blood vessels is an important finding, since this could contribute to dNP progression and supports the theory of receptor up-regulation of denervated structures. The implications of this α-upregulation should be examined in further studies.