Cross-Tolerance to Etorphine Differentiates μ-Opioid Agonists in a Rat Tail Withdrawal Assay

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Abstract
Opioids are differentially sensitive to receptor alteration by repeated agonist treatment. The present experiment tests the hypothesis that these differences are related to opioid agonist efficacy by examining cross-tolerance among the analgesic effects of etorphine and several other μ agonists. These include high-efficacy agonists etorphine and l-methadone, and intermediate- to low-efficacy agonists morphine, buprenorphine, and dezocine. The rat tail withdrawal assay is used to measure analgesia. In this procedure, rats are placed in restrainers and the latency for tail withdrawal from 55°C water is measured. β-Funaltrexamine (5.0 mg/kg, SC) pretreatment decreased the maximal analgesic response produced by dezocine but not etorphine, l-methadone, morphine, or buprenorphine. These data suggest that dezocine is the lowest efficacy agonist used in the present study. Daily treatment with 0.0064 mg/kg etorphine for 7 days increased the ED50 values for morphine, buprenorphine, and dezocine by three-, six-, and ninefold, respectively. Additionally, chronic etorphine treatment increased the dose of morphine and buprenorphine that produced a 100% maximal possible effect. No dose of dezocine produced 100% maximum possible effect in etorphine-treated rats. Daily treatment with 0.0064 mg/kg per day etorphine d id not shift the etorphine or l-methadone dose–response curves. Higher chronic doses of etorphine could not be tested due to toxicity. The present findings indicate that cross-tolerance between etorphine and other μ agonists is greatest for the low-efficacy agonists, buprenorphine and dezocine. These data support the hypothesis that the magnitude of tolerance is inversely related to the relative efficacy of the agonist tested.

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