Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and κ-opioid receptors in rat spinal cord nociceptive reflexes

Abstract

Antinociception induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9±13% of control) but not with low doses of naloxone (27±8% of control), indicating an involvement of κ-opioid but not µ-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of κ-opioid but not µ-opioid receptors in inflammation. In addition, coadministration of CPA and κ-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain

“…In a rat with spinal cord injury (SCI), it was demonstrated a supra-additive interaction between the adenosine A 1 AR agonist R-PIA and morphine in the reduction in mechanical allodynia-like behavior [ 47 ]. In spinal cord neuronal nociceptive responses, the antinociceptive effects of the A 1 AR agonist CPA were associated with activation of κ-opioid receptors since the reversal of the CPA effect was observed with norbinaltorphimine (a selective κ-opioid receptor antagonist) but not with low doses of µ-opioid antagonist naloxone [ 48 ]. While the opioid antagonist naltrexone did not affect the antinociception induced by CPA in the formalin test, the activation of A 1 or A 2A AR counteracted the µ-opioid receptor increase induced by formalin in the spinal cord, confirming the interaction between adenosinergic and opioid systems [ 49 ].…”

The Agonist of Adenosine A1 Receptor Induced Desensitization of delta Opioid receptor-mediated Raf-1/MEK/ERK Signaling by Feedback Phosphorylation of Raf-1-Ser289/296/301

“…Our ndings regarding the crosstalk between A 1 R-and DOR-mediated signaling pathways represent a new mechanism that control physiologic functions related to opioid receptors, including their nociceptive and non-nociceptive roles. For example, it has been discovered that activation of adenosine receptors was able to modulate the effect and tolerance of the opioid receptor system, which result in potentiation of morphine antinociception [23], visceral antinociception [24] and spinal cord nociceptive re exes [25]. Moreover, since DOR has emerged as a promising target for pain treatment [26] due to the analgesic potency of its own agonists [27] or contribution to the antinociception effects of other drugs [18], investigations on mechanisms that control DOR activity, such as its interaction with A 1 R, is of great value in development of novel strategies for pain management.…”