Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV.

BACKGROUND: Mechanical alloknesis (or innocuous mechanical stimuli-evoked itch) often occurs in dry skin-based disorders such as atopic dermatitis and psoriasis. However, the molecular and cellular mechanisms underlying mechanical alloknesis remain unclear. We recently reported the involvement of CD26 in the regulation of psoriatic itch. This molecule exhibits dipeptidyl peptidase IV (DPPIV) enzyme activity and exerts its biologic effects by processing various substances, including neuropeptides. OBJECTIVE: The aim of the present study was to investigate the peripheral mechanisms of mechanical alloknesis by using CD26/DPPIV knockout (CD26KO) mice. METHODS: We applied innocuous mechanical stimuli to CD26KO or wild-type mice. The total number of scratching responses was counted as the alloknesis score. Immunohistochemical and behavioral pharmacologic analyses were then performed to examine the physiologic activities of CD26/DPPIV or endomorphins (EMs), endogenous agonists of µ-opioid receptors. RESULTS: Mechanical alloknesis was more frequent in CD26KO mice than in wild-type mice. The alloknesis score in CD26KO mice was significantly reduced by the intradermal administration of recombinant DPPIV or naloxone methiodide, a peripheral µ-opioid receptor antagonist, but not by that of mutant DPPIV without enzyme activity. EMs (EM-1 and EM-2), selective ligands for µ-opioid receptors, are substrates for DPPIV. Immunohistochemically, EMs were located in keratinocytes, fibroblasts, and peripheral sensory nerves. Behavioral analyses revealed that EMs preferentially provoked mechanical alloknesis over chemical itch. DPPIV-digested forms of EMs did not induce mechanical alloknesis. CONCLUSION: The present results suggest that EMs induce mechanical alloknesis at the periphery under the enzymatic control of CD26/DPPIV.

Complex formation and functional interaction between adenosine A1 receptor and type-1 metabotropic glutamate receptor.

The adenosine A1 receptor (A1R) is a G protein-coupled receptor (GPCR) for adenosine, a ubiquitous neuromodulator, and thus regulates neuronal excitability, as well as arousal and sensitivity to pain. In addition, we have previously described a new mode of action for A1R: in cerebellar Purkinje cells, its activation attenuates neuronal responses to glutamate, as mediated by the type-1 metabotropic glutamate receptor (mGluR1). mGluR1 is also a GPCR, and elicits such responses as long-term depression of the postsynaptic response to glutamate, a cellular basis for cerebellar motor learning. Here, we explore in greater detail the interaction between A1R and mGluR1 using non-neuronal cells. Co-immunoprecipitation and Förster resonance energy transfer (FRET) analysis reveal that A1R and mGluR1 form a complex. Furthermore, we found that mGluR1 activation inhibits A1R signaling, as measured by changes in intracellular cAMP. These findings demonstrate that A1R and mGluR1 have the intrinsic ability to form a heteromeric complex and mutually modulate signaling. This interaction may represent a new form of intriguing GPCR-mediated cellular responses.