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 (α1-AR) hyperresponsiveness contributes to pain in dNP. The aim of our study was to quantify α1-AR expression using immunohistochemistry in skin biopsies of nine patients with painful diabetic neuropathy compared to 10 healthy controls. Additionally, the association between α1-AR expression and activation with spontaneous and sympathetically maintained pain (SMP) induced by intradermal injection of the α1-agonist phenylephrine was investigated. For control purposes the α2-agonist clonidine was injected in a different session.
      We found that dermal nerve density was significantly lower in dNP than in controls. However, α1-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 α1-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 α1-upregulation should be examined in further studies.



      α1-AR (alpha-1 adrenoceptor), α–SMA (α-smooth muscle), CRPS (complex regional pain syndrome), dNP (diabetic neuropathy), PBS (phosphate buffered saline), SMP (sympathetically maintained pain)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Abbott C.A.
        • Malik R.A.
        • van Ross E.R.
        • Kulkarni J.
        • Boulton A.J.
        Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K.
        Diabetes Care. 2011; 34: 2220-2224
        • Ali Z.
        • Raja S.N.
        • Wesselmann U.
        • Fuchs P.N.
        • Meyer R.A.
        • Campbell J.N.
        Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain.
        Pain. 2000; 88: 161-168
        • Bickel A.
        • Butz M.
        • Schmelz M.
        • Handwerker H.O.
        • Neundorfer B.
        Density of sympathetic axons in sural nerve biopsies of neuropathy patients is related to painfulness.
        Pain. 2000; 84: 413-419
        • Cannon W.B.
        • Rosenbleuth A.
        The Supersensitivity of Denervated Structures. A Law of Denervation. MacMillan, editor.
        MacMillan, New York1949
        • Cheng J.
        • Daftari A.
        • Zhou L.
        Sympathetic blocks provided sustained pain relief in a patient with refractory painful diabetic neuropathy.
        Case Rep. Anesthesiol. 2012; 285328: 2012
        • Choi B.
        • Rowbotham M.C.
        Effect of adrenergic receptor activation on post-herpetic neuralgia pain and sensory disturbances.
        Pain. 1997; 69: 55-63
        • Daousi C.
        • Benbow S.J.
        • Woodward A.
        • MacFarlane I.A.
        The natural history of chronic painful peripheral neuropathy in a community diabetes population.
        DiabetMed. 2006; 23: 1021-1024
        • Dawson L.F.
        • Phillips J.K.
        • Finch P.M.
        • Inglis J.J.
        • Drummond P.D.
        Expression of alpha1-adrenoceptors on peripheral nociceptive neurons.
        Neuroscience. 2011; 175: 300-314
        • Delorey D.S.
        • Clifford P.S.
        • Mittelstadt S.
        • Anton M.M.
        • Kluess H.A.
        • Tune J.D.
        • et al.
        The effect of aging on adrenergic and nonadrenergic receptor expression and responsiveness in canine skeletal muscle.
        J. Appl. Physiol. (1985). 2012; 112: 841-848
        • Ding Y.
        • Yao P.
        • Li H.
        • Zhao R.
        • Zhao G.
        Evaluation of combined radiofrequency and chemical blockade of multi-segmental lumbar sympathetic ganglia in painful diabetic peripheral neuropathy.
        J. Pain Res. 2018; 11: 1375-1382
        • Drummond P.D.
        Neuronal changes resulting in up-regulation of alpha-1 adrenoceptors after peripheral nerve injury.
        Neural Regen. Res. 2014; 9: 1337-1340
        • Drummond P.D.
        • Dawson L.F.
        • Finch P.M.
        • Drummond E.S.
        • Wood F.M.
        • Fear M.W.
        Up-regulation of cutaneous alpha1-adrenoceptors after a burn.
        Burns. 2015; 41: 1227-1234
        • Drummond E.S.
        • Maker G.
        • Birklein F.
        • Finch P.M.
        • Drummond P.D.
        Topical prazosin attenuates sensitivity to tactile stimuli in patients with complex regional pain syndrome.
        EurJPain. 2016; 20: 9
        • Drummond P.D.
        • Morellini N.
        • Finch P.M.
        • Birklein F.
        • Knudsen L.F.
        Complex regional pain syndrome: intradermal injection of phenylephrine evokes pain and hyperalgesia in a subgroup of patients with upregulated alpha1-adrenoceptors on dermal nerves.
        Pain. 2018; 159: 2296-2305
        • Feldman E.L.
        • Nave K.A.
        • Jensen T.S.
        • Bennett D.L.H.
        New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain.
        Neuron. 2017; 93: 1296-1313
        • Finch P.M.
        • Drummond E.S.
        • Dawson L.F.
        • Phillips J.K.
        • Drummond P.D.
        Up-regulation of cutaneous alpha1 -adrenoceptors in complex regional pain syndrome type I.
        Pain Med. 2014; 15: 1945-1956
        • Gibbs G.F.
        • Drummond P.D.
        • Finch P.M.
        • Phillips J.K.
        Unravelling the pathophysiology of complex regional pain syndrome: focus on sympathetically maintained pain.
        ClinExpPharmacolPhysiol. 2008; 35: 717-724
        • Grando S.A.
        • Pittelkow M.R.
        • Schallreuter K.U.
        Adrenergic and cholinergic control in the biology of epidermis: physiological and clinical significance.
        J. Invest. Dermatol. 2006; 126: 1948-1965
        • Harden R.N.
        • Oaklander A.L.
        • Burton A.W.
        • Perez R.S.
        • Richardson K.
        • Swan M.
        • et al.
        Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition.
        Pain Med. 2013; 14: 180-229
        • Kavelaars A.
        Regulated expression of alpha-1 adrenergic receptors in the immune system.
        Brain Behav. Immun. 2002; 16: 799-807
        • Knudsen L.F.
        • Terkelsen A.J.
        • Drummond P.D.
        • Birklein F.
        Complex regional pain syndrome: a focus on the autonomic nervous system.
        Clin. Auton. Res. 2019; 29: 457-467
        • Loavenbruck A.
        • Sit N.
        • Provitera V.
        • Kennedy W.
        High-resolution axon reflex sweat testing for diagnosis of neuropathy.
        Clin. Auton. Res. 2019; 29: 55-62
        • Malik R.A.
        • Newrick P.G.
        • Sharma A.K.
        • Jennings A.
        • Ah-See A.K.
        • Mayhew T.M.
        • et al.
        Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy.
        Diabetologia. 1989; 32: 92-102
        • Morellini N.
        • Finch P.M.
        • Goebel A.
        • Drummond P.D.
        Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome.
        Pain. 2018; 159: 2021-2029
        • Orstavik K.
        • Jorum E.
        Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy.
        Neurosci. Lett. 2010; 470: 180-184
        • Pelliccia F.
        • Kaski J.C.
        • Crea F.
        • Camici P.G.
        Pathophysiology of Takotsubo syndrome.
        Circulation. 2017; 135: 2426-2441
        • Quattrini C.
        • Harris N.D.
        • Malik R.A.
        • Tesfaye S.
        Impaired skin microvascular reactivity in painful diabetic neuropathy.
        Diabetes Care. 2007; 30: 655-659
        • Raputova J.
        • Srotova I.
        • Vlckova E.
        • Sommer C.
        • Uceyler N.
        • Birklein F.
        • et al.
        Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study.
        Pain. 2017; 158: 2340-2353
        • Rouppe van der Voort C.
        • Kavelaars A.
        • van de Pol M.
        • Heijnen C.J.
        Neuroendocrine mediators up-regulate alpha1b- and alpha1d-adrenergic receptor subtypes in human monocytes.
        J. Neuroimmunol. 1999; 95: 165-173
        • Sato J.
        • Perl E.R.
        Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury.
        Science. 1991; 251: 1608-1610
        • Skalli O.
        • Ropraz P.
        • Trzeciak A.
        • Benzonana G.
        • Gillessen D.
        • Gabbiani G.
        A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation.
        J. Cell Biol. 1986; 103: 2787-2796
        • Stino A.M.
        • Rumora A.E.
        • Kim B.
        • Feldman E.L.
        Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy.
        J. Peripher. Nerv. Syst. 2020; 25: 76-84
        • Tack C.J.
        • van Gurp P.J.
        • Holmes C.
        • Goldstein D.S.
        Local sympathetic denervation in painful diabetic neuropathy.
        Diabetes. 2002; 51: 3545-3553
        • Teasell R.W.
        • Arnold J.M.
        Alpha-1 adrenoceptor hyperresponsiveness in three neuropathic pain states: complex regional pain syndrome 1, diabetic peripheral neuropathic pain and central pain states following spinal cord injury.
        Pain Res. Manag. 2004; 9: 89-97
        • Tesfaye S.
        • Malik R.
        • Harris N.
        • Jakubowski J.J.
        • Mody C.
        • Rennie I.G.
        • et al.
        Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis).
        Diabetologia. 1996; 39: 329-335
        • Torebjork E.
        • Wahren L.
        • Wallin G.
        • Hallin R.
        • Koltzenburg M.
        Noradrenaline-evoked pain in neuralgia.
        Pain. 1995; 63: 11-20
        • Verdugo R.J.
        • Campero M.
        • Ochoa J.L.
        Phentolamine sympathetic block in painful polyneuropathies. II. Further questioning of the concept of ‘sympathetically maintained pain’.
        Neurology. 1994; 44: 1010-1014
        • Wallengren J.
        • Badendick K.
        • Sundler F.
        • Håkanson R.
        • Zander E.
        Innervation of the skin of the forearm in diabetic patients: relation to nerve function.
        Acta Derm. Venereol. 1995; 75: 37-42
        • Wijaya L.K.
        • Stumbles P.A.
        • Drummond P.D.
        A positive feedback loop between alpha(1)-adrenoceptors and inflammatory cytokines in keratinocytes.
        Exp. Cell Res. 2020; 391112008
        • Wijaya L.K.
        • Stumbles P.A.
        • Drummond P.D.
        Tumor necrosis factor α induces α(1B)-adrenergic receptor expression in keratinocytes.
        Cytokine. 2020; 125154851