Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats

Abstract

Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100Hz) or low frequency (4Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner.

Fig. 1

Experimental timeline for the systemic administration of drugs.

Fig. 2

Experimental timeline for the intrathecal administration of drugs.

Fig. 3

Systemic blockade of CCK receptors prevents the development of tolerance to high and low frequency TENS. Bar graph representing mechanical withdrawal threshold of the knee joint (A) and paw (B) from animals receiving TENS treatment combined with proglumide or vehicle. Mechanical withdrawal thresholds are illustrated prior to induction of inflammation (baseline), before (pre), and after application of TENS (post). Data are represented as means ± SEM. P value <0.05 was considered statistically significant. ^*Significantly different from baseline; ^†significantly different from sham TENS, and vehicle controls on D4.

Fig. 4

Intrathecal blockade of CCK-A receptors prevents the development of tolerance to high frequency TENS, but not low frequency TENS. Bar graph representing mechanical withdrawal threshold of the knee joint (A) and paw (B) from animals receiving TENS treatment combined with lorglumide or vehicle. Mechanical withdrawal thresholds are illustrated prior to induction of inflammation (baseline), before (pre), and after application of TENS (post). Data are represented as means ± SEM. P value <0.05 was considered statistically significant. ^*Significantly different from baseline time; ^†significantly different from sham TENS and vehicle controls on D4.

Fig. 5

Intrathecal blockade of CCK-B receptors prevents the development of tolerance to low frequency TENS, but not high frequency TENS. Bar graph representing mechanical withdrawal threshold of the knee joint (A) and paw (B) from animals receiving TENS treatment combined with itriglumide or vehicle. Mechanical withdrawal thresholds are illustrated prior to induction of inflammation (baseline), before (pre), and after application of TENS (post). Data are represented as means ± SEM. P value <0.05 was considered statistically significant. ^*Significantly different from baseline time; ^†significantly different from sham TENS and vehicle controls on D4.

Fig. 6

Dose–response curves for SNC-80 and DAMGO. Line graphs representing paw withdrawal threshold after intrathecal injection of increasing doses of SNC-80 (A) and DAMGO (B) in groups receiving TENS treatment combined with CCK receptor antagonists or vehicle. After administration of SCN-80, groups treated with high TENS and vehicle, the withdrawal thresholds were lower than those treated with high TENS and lorglumide^*. Following administration of DAMGO, groups treated with low TENS and vehicle, the withdrawal thresholds were lower than those treated with low TENS and itriglumide^*.