Adenosine-A1 receptor agonist induced hyperalgesic priming type II

Abstract

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-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt) induces a model of the 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 E2 (PGE2). However, Type II hyperalgesic priming differs from Type I in being rapidly induced, protein kinase A (PKA), rather than PKCε 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, N6-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 PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced Type II priming, in which it depends on the β/γ 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.

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

“…Animals regained consciousness approximately 1 minute after completion of the injection. The use of AS ODN to manipulate the expression of proteins, essential for their role in nociceptor sensitization, is well supported by previous studies by others (Song et al, 2009, Su et al, 2011, Quanhong et al, 2012, Sun et al, 2013), as well as our group (Parada et al, 2003, Bogen et al, 2012, Alvarez et al, 2014, Araldi et al, 2015, 2016a, Ferrari et al, 2016). …”

“…Of note, we have previously shown that agonists at two other Gi-protein-coupled receptors, mu-opioid and A1-adenosine, can also induce mechanical hyperalgesia; however, the hyperalgesia induced by agonists at these latter two Gi-GPCRs requires repeated administration (Araldi et al, 2015, 2016a). …”

“…Paradoxically, we found that sumatriptan-induced hyperalgesia is mediated by the α i subunit of the heterotrimeric Gi-protein and by PKA. Of note, the ability of pertussis toxin (a Gi-protein inhibitor) to prevent sumatriptan-induced hyperalgesia is also characteristic of the mechanical hyperalgesia induced by repeated injections of the A1-adenosine receptor agonist CPA (Araldi et al, 2016a), but not by repeated injections of the mu-opioid receptor agonist DAMGO (Araldi et al, 2015). …”

“…The following drugs were used: sumatriptan succinate (prototypical 5-HT 1B and 5-HT 1D receptor agonist), CP-93129 dihydrochloride hydrate [a selective 5-HT 1B receptor agonist; (Araldi et al, 2016b)] and pertussis toxin [PTX; Gi-protein inhibitor; (Araldi et al, 2015, 2016b, a)] from Sigma-Aldrich (St. Louis, MO, USA); H-89 dihydrochloride [inhibitor of protein kinase A (PKA); (Araldi et al, 2015, 2016a, b)] from Santa Cruz Biotechnology (Dallas, TX, USA); BRL 15572 [5-HT 1D receptor antagonist; (Araldi et al, 2016b)], L-694,247 [a selective 5-HT 1D receptor agonist; (Araldi et al, 2016b)] and NAS-181 [5-HT 1B receptor antagonist; (Araldi et al, 2016b)] from Tocris Bioscience (Avonmouth, Bristol, UK); and G-36 [GPR30 receptor antagonist; (Alvarez et al, 2014)] from Azano Pharmaceuticals (Albuquerque, NM, USA).…”

“…The dose and timing of IB4-saporin administration were chosen based on previous reports from our group and others (Vulchanova et al, 2001, Nishiguchi et al, 2004, Joseph et al, 2008, Joseph and Levine, 2010, Araldi et al, 2015, 2016b, a). …”