Development of opioid tolerance with repeated transcutaneous electrical nerve stimulation administration

The analgesia produced by low and high frequency transcutaneous electrical nerve stimulation (TENS) is mediated by the release of mu- or delta-opioids, respectively in the central nervous system. Repeated administration of either mu- or delta-opioid agonists induce opioid analgesic tolerance. Thus, we tested if repeated administration of TENS (either low or high frequency) in rats leads to a development of tolerance to its antihyperalgesic effects with a corresponding cross-tolerance to mu- and delta-opioid agonists. Unilateral knee joint inflammation (3% carrageenan) was induced in adult Sprague-Dawley rats. Either low (4 Hz) or high frequency (100 Hz) TENS was administered for 6 days (20 min daily) to the inflamed knee joint under halothane anesthesia. The no TENS controls were administered anesthesia only for the same period. Withdrawal threshold to mechanical stimuli was measured before and after administration of TENS on each day and also on the sixth day. A separate group of animals was tested for tolerance to either the mu-opioid agonist, morphine (1.32, 3.95, 13.2 nmol/10 ml, intrathecal (i.t.)) or the delta-opioid agonist, SNC-80 (6, 20, 60, 120 nmol/10 ml, i.t.) 30 min after i.t. administration. The reduced mechanical withdrawal threshold following the induction of inflammation was reversed by the application of TENS. However, repeatedly administering either low or high frequency TENS for 6 days, lead to a diminution in its effectiveness in reversing the ipsilateral secondary mechanical hyperalgesia by the fourth day. The effects of morphine in the low and SNC-80 in the high frequency TENS groups were significantly less than the group that did not receive TENS. On the other hand, morphine and SNC-80 were similar to the no TENS control in the high and low frequency TENS groups, respectively. Thus, repeated administration of low and high frequency TENS leads to a development of opioid tolerance with a corresponding cross-tolerance to i.t. administered mu- and delta-opioid agonists, respectively. Clinically, it can be inferred that a treatment schedule of repeated daily TENS administration should be avoided to possibly obviate the induction of tolerance.