α2δ-1-Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

Background: Chronic use of mu-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid- induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. alpha 2 delta-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that alpha 2 delta-1-bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance. Methods: Rats (5 mg/kg) and wild-type and alpha 2 delta-1-knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein-protein interactions. Results: Chronic morphine treatment in rats increased alpha 2 delta-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between alpha 2 delta-1 and N-methyl-d-aspartate receptors by 1.5 +/- 0.3 fold (means +/- SD, P = 0.009, n = 6) and the prevalence of alpha 2 delta-1-bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting alpha 2 delta-1 with gabapentin or genetic knockout of alpha 2 delta-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the alpha 2 delta-1-Nmethyl- d-aspartate receptor interaction with an alpha 2 delta-1 C terminus-interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an alpha 2 delta-1 C terminus-interfering peptide or alpha 2 delta-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine's analgesic effect during 8 days of morphine treatment. Conclusions: alpha 2 delta-1-Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level.