Abstract Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the α2A-AR. Drugs were administered intrathecally in wild type (WT) and α2A-knock-out (KO) mice and antinociception was measured using the hot water tail immersion or substance P behavioral assays. The α2A-AR agonist clonidine was less effective in α2A-KO mice in both assays. The absence of the α2A-AR resulted in 10-70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in α2A-KO mice, indicating that the α2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in α2A-KO mice, suggesting that endogenous norepinephrine acts through the α2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free α2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied α2A-ARs potentiate opioid analgesia, while non-occupied α2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management.
Bibliographical noteFunding Information:
This work was supported by Canadian Institutes for Health Research (CIHR) operating grants ( MOP-86691 to LSS and MOP-130309 to TEH), National Institutes of Health/ National Institute on Drug Abuse Grants # R01 DA015438 to GLW and # K01 DA000509 to CAF, funds from the Canadian Foundation for Innovation ( CFI 13691 ) to LSS, a Chercheur-Boursier award from Fonds de Recherche en Santé du Québec (FRSQ) to LSS and Réseau de recherche en santé buccodentainre et osseuse (RSBO) infrastructure support to LSS. AJCD received studentship support from CIHR, the McGill University Integrated Program in Neuroscience (IPN) and the Louise and Alan Edwards Foundation and travel support from the Quebec Pain Research Network and the IPN. LD is the Canada Excellence Research Chair in Personalized Pain Medicine (CERC 08) and received funds from the Canada Foundation for Innovation ( CFI 32151 ). Funding sources had no role in the planning, execution, analysis and interpretation of experiments, or in the manuscript preparation.
- Opioid receptor
- Spinal cord