α2C-Adrenergic Receptors Mediate Spinal Analgesia and Adrenergic-Opioid Synergy

Abstract

The ␣ 2A -adrenergic receptor (AR) subtype mediates antinociception induced by the ␣ 2 AR agonists clonidine, dexmedetomidine, norepinephrine, and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304) as well as antinociceptive synergy of UK-14,304 with opioid agonists [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin and deltorphin II. Differential localization of ␣ 2 -adrenergic (␣ 2A -, ␣ 2B -, ␣ 2C -) and opioid (-, ␦-, -) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline 1 /␣ 2 -adrenergic receptor analgesic, moxonidine, to test for involvement of ␣ 2B -and ␣ 2C ARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on ␣ 2A AR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of ␣ 2A AR (D79N-␣ 2A AR) and ␣ 2C AR knockout (KO) mice. The potency of moxonidine was not altered in ␣ 2B KO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective ␣ 2 -receptor antagonist SK&F 86466 in both D79N-␣ 2A mice and ␣ 2C KO mice, indicating that ␣ 2 AR activation is required in the absence of either ␣ 2A -or ␣ 2C AR. Spinal administration of antisense oligodeoxynucleotides directed against the ␣ 2C AR decreased both ␣ 2C AR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-␣ 2A mice but not in the ␣ 2C AR-KO mice. These results confirm that the ␣ 2C AR subtype contributes to spinal antinociception and synergy with opioids.

Synergistic and additive interactions of the cannabinoid agonist CP55,940 with μ opioid receptor and α2‐adrenoceptor agonists in acute pain models in mice

“…Both supraspinal and spinal pathways are involved in a 2 -adrenoceptor-mediated analgesia. The spinal antinociceptive actions of a 2 -adrenoceptors are mediated mainly by the a 2A -subtype (Jones et al, 1982;Khan et al, 1999;Kamibayashi & Maze, 2000;Malmberg et al, 2001), although a 2C -adrenoceptors also contribute (Fairbanks et al, 2002). Dexmedetomidine is a selective a 2 -adrenoceptor agonist currently approved for clinical use under intensive care conditions (Khan et al, 1999;Coursin & Maccioli, 2001).…”

Modulation of pain transmission by G-protein-coupled receptors

“…In the hot-plate test, the antinociceptive effect of the α 2 -adrenergic receptor agonist UK14,304 in mice is abolished by the α 2A -preferring receptor antagonists RX821002 or BRL44408 (Millan, 1992). Using α 2A -, α 2B -, and α 2C -subtype knockout mice, it has been shown that the α 2A -adrenergic receptors are primarily involved in the analgesic effect produced by α 2 -adrenergic receptor agonists (Stone et al, 1997;Fairbanks et al, 2002;Mansikka et al, 2004). Furthermore, the α 2C , but not α 2B -, adrenergic receptors in the spinal cord contribute to the antinociceptive effect produced by intrathecal injection of an imidazoline/α 2 -adrenergic receptor agonist, moxonidine (Fairbanks et al, 2002).…”

“…Using α 2A -, α 2B -, and α 2C -subtype knockout mice, it has been shown that the α 2A -adrenergic receptors are primarily involved in the analgesic effect produced by α 2 -adrenergic receptor agonists (Stone et al, 1997;Fairbanks et al, 2002;Mansikka et al, 2004). Furthermore, the α 2C , but not α 2B -, adrenergic receptors in the spinal cord contribute to the antinociceptive effect produced by intrathecal injection of an imidazoline/α 2 -adrenergic receptor agonist, moxonidine (Fairbanks et al, 2002). These studies demonstrate that α 2A -and α 2C -adrenergic receptors are probably essential for the antinociceptive effect induced by α 2 -adrenergic receptor agonists.…”

Intrathecal Clonidine as Spinal Anaesthesia Adjuvant — Is there a Magical Dose?

“…They were able to demonstrate that the alpha2A subtype receptor is the primary mediator of alpha2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids, and concluded that combination therapies targeting the alpha2A receptor and opioid receptors may be useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements. Although others have found that the alpha2C adrenergic receptor subtype contributes to this synergy, [27] Chabot-Doré and coworkers [28] confirmed that although other opioid receptors can interact synergistically with alpha2 receptors agonists, Delta opioid receptor is sufficient for spinal opioid-adrenergic interactions. Protein kinase is needed for this analgesic synergy.…”