Plasticity of α2-adrenergic spinal antinociception following nerve injury: Selective, bidirectional interaction with the delta opioid receptor

• We show synaptic up-regulation of alpha-2aR in dorsal horn neurons in SNL rats.
• Alpha-2aR is shown to modulate dorsal horn potentials evoked by noxious input.
• Alpha-2aR-mediated modulation depends on opioid delta- but not mu-receptors.
• Alpha-2aR enhances delta- but not mu-opioid receptor-modulation of hyperexcitation.
• Chronic treatment with alpha-2aR agonist enhances delta-opioid behavioral analgesia.

Interactions of opioid receptors with other receptor families can be made use of to improve analgesia and reduce adverse effects of opioid analgesics. We investigated interactions of the α2-adrenergic receptor (α2AR) with opioid receptors of the mu (MOR) and delta (DOR) types in the spinal dorsal horn in an animal model of neuropathic pain induced by spinal nerve ligation. Nine days after nerve injury, immunoreactivity for the α2AR subtype A (α2AAR) was increased both in tissue homogenates and at pre- and post-synaptic sites in transverse sections. The efficacy of spinally administered α2AAR agonist guanfacine at reducing C-fiber-evoked field potentials was increased in nerve-ligated rats. This reducing effect was impaired by simultaneous administration of DOR antagonist naltrindole, but not MOR antagonist CTOP, suggesting that concurrent DOR activation was required for α2AAR-mediated inhibition. While DOR agonist deltorphin II and MOR agonist DAMGO both effectively depressed C-fiber-evoked spinal field potentials, DOR- but not MOR-mediated depression was enhanced by subclinical guanfacine. In conscious, nerve-ligated rats, chronically administered deltorphin II produced stable thermal and mechanical antinociception over the 9 following days after nerve injury without apparent signs of habituation. Such an effect was dramatically enhanced by co-administration of a low dose of guanfacine, which reversed thermal and mechanical thresholds to levels near those prior to injury. The results suggest that spinal, α2AAR-mediated antinociception is increased after nerve injury and based on DOR co-activation. We demonstrate in vivo that α2AAR/DOR interaction can be exploited to provide effective behavioral antinociception during neuropathic pain.