Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords

Abstract

Background:We determined the role of presynaptic N-methyl-D-aspartate receptor (NMDAR) activity in spinal cords in opioid-induced hyperalgesia and tolerance. Results: Chronic opioid increases presynaptic NMDAR activity at primary sensory nerve terminals through protein kinase C. Conclusion: Increased presynaptic NMDAR activity potentiates nociceptive input and is responsible for opioid hyperalgesia and tolerance. Significance: Understanding mechanisms of increased NMDAR activity is important for improving opioid therapies.

Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons

“…To activate the device, a foot pedal was pressed, triggering a motor that applied a constantly increasing force on a linear scale. When the animal displayed pain by either withdrawing its paw or vocalizing, the pedal was immediately released, and the nociceptive threshold of the animal was read on the scale (24,28,29). Each trial was repeated two or three times at ϳ2-min intervals, and the mean value was used as the force to produce withdrawal responses.…”

“…We filled a glass pipette (5-10 M⍀) with an internal solution containing 135.0 mM potassium gluconate, 5.0 mM tetraethylammonium chloride, 2.0 mM MgCl 2 , 0.5 mM CaCl 2 , 5.0 mM HEPES, 5.0 mM EGTA, 5.0 mM ATP-Mg, 0.5 mM Na-GTP, 1.0 mM guanosine 5Ј-O-(2-thiodiphosphate), and 10.0 mM lidocaine N-ethyl bromide (adjusted to pH 7.2-7.4 with 1 M KOH, 290 -300 mosmol). Guanosine 5Ј-O-(2-thiodiphosphate) was included in the pipette recording solution to block the postsynaptic effect of the opioids (10,28). The input resistance was monitored, and the recording was abandoned if it changed more than 15%.…”

“…Behavioral Assessment of Tactile Allodynia and Hyperalgesia-Behavioral tests were conducted as described previously (24,28). In brief, to detect tactile allodynia, we applied von Frey filaments to the left hind paw of the animals (ipsilateral to SNL or SNI).…”

Casein Kinase II RegulatesN-Methyl-d-Aspartate Receptor Activity in Spinal Cords and Pain Hypersensitivity Induced by Nerve Injury

“…All signals were recorded using an amplifier (MultiClamp700B; Axon Instruments Inc., Union City, CA), filtered at 1 to 2 kHz, digitized at 10 kHz, and stored for offline analysis. We used electrical stimulation (0.2 milliseconds, 0.6 mA, and 0.1 Hz) of the dorsal root to evoke monosynaptic excitatory postsynaptic currents (EPSCs) (Zhou et al, 2008(Zhou et al, , 2010Zhao et al, 2012). The AMPAR [a-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor]-EPSCs were recorded at a holding potential of -60 mV in the presence of 10 mM bicuculline and 1 mM strychnine.…”

“…For this reason, we used the area under the curve to compare the changes in NMDARmediated mEPSCs. In some neurons, NMDAR currents were elicited by puff application of 100 mM NMDA (Zhao et al, 2012) to the recorded neuron using a positive pressure system (4 psi, 15 milliseconds; Toohey Company, Fairfield, NJ). The tip of the puff pipette was place 150 mm away from the recorded neuron, and the recordings were performed using the extracellular solution containing 0.1 mM Mg 21 , 10 mM glycine, and 1 mM tetrodotoxin at a holding potential of 260 mV and using the pipette internal solution containing the following (in mM): 110.0 Cs 2 SO 4 , 2.0 MgCl 2 , 0.1 CaCl 2 , 1.1 EGTA, 10.0 HEPES, 2.0 MgATP, and 0.3 Na 2 GTP (pH was adjusted to 7.25 with 1.0 M CsOH; 280-300 mOsm).…”