Blockade of NMDA receptors prevents analgesic tolerance to repeated transcutaneous electrical nerve stimulation (TENS) in rats.
Repeated daily application of transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the antihyperalgesia produced by TENS. Since N-methyl-D-aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists, we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minutes daily at high-frequency (100 Hz), low-frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg to 0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation and before and after TENS treatment for 4 days. On day 1, TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4, TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle, demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4, demonstrating that tolerance did not develop. Vehicle-treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors.


CONCLUSIONS
Observed tolerance to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan.
Graduate Program in Physical Therapy and Rehabilitation Science, Neuroscience Graduate Program, Pain Research Program, University of Iowa, Iowa City, Iowa 52242, USA.
Priyanka M
PM
Hingne
Kathleen A
KA
Sluka
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001549:Benzamides / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology* / Q000528:radiation effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D007719:Knee Joint / Q000187:drug effects; D008297:Male; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D004561:Transcutaneous Electric Nerve Stimulation / Q000379:methods*
D000700:Analgesics; D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016291:Dizocilpine Maleate