Journal
PAIN
Volume 157, Issue 3, Pages 698-709Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000000421
Keywords
Hyperalgesic priming; Hyperalgesia; A1-adenosine receptor; alpha(1) subunit; Chronic pain
Categories
Funding
- National Institutes of Health (NIH) [NS084545]
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We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E-2 (PGE(2)). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKC epsilon dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that, as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N-6-cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced type II hyperalgesic priming. In this study, we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms, as MOR-agonist induced priming. However, the prolongation of PGE(2) hyperalgesia induced by repeated administration of CPA depends on G-protein alpha(1) subunit activation, differently from DAMGO-induced type II priming, in which it depends on the beta/gamma subunit. These data implicate a novel form of Gi-protein signaling pathway in the type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor.
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