Ketamine Tolerance in Sprague-Dawley Rats after Chronic Administration of Ketamine, Morphine, or Cocaine

Abstract

Ketamine is one of the most commonly used anesthetics in human and veterinary medicine, but its clinical effectiveness is often compromised due to tolerance to its anesthetic effects. Although ketamine tolerance has been demonstrated in a number of behavioral measures, no published work has investigated tolerance to ketamine's anesthetic effects other than duration of anesthesia. In addition, a reported practice in anesthesiology is to alter anesthetic doses for procedures when the patient has a history of drug abuse. Empirically investigating the effects of administration of a drug of abuse on ketamine's potency and efficacy to produce anesthesia could help in the creation of anesthetic plans that maximize safety for both clinicians and patients. The goal of the current study was to test the effects of repeated administration of ketamine, morphine, or cocaine on ketamine's ability to produce anesthesia. In 2 studies, male Sprague-Dawley rats received daily injections of ketamine (32 or 100 mg/kg IP), morphine (3.2 or 5.6 mg/kg IP), or cocaine (3.2 or 10 mg/kg IP) for 14 consecutive days and then were tested on day 15 for ketamine-induced anesthesia by using a cumulative-dosing procedure (32 to 320 mg/kg IP). Chronic treatment with either ketamine or morphine-but not cocaine-produced tolerance to ketamine's anesthetic effects in a dose-dependent manner. These results suggest that ketamine's clinical effectiveness as an anesthetic will vary as a function of its history of use. Furthermore, given that chronic morphine administration produced tolerance to ketamine's anesthetic effects, various pain medications may reduce ketamine's effectiveness for anesthesia.

Figure 1.

Measures of sedation.

Figure 2.

(A) Percentage of subjects in plane III anesthesia as a function of the cumulative ketamine dose. (B) Latency (h) to recovery (mean ± SEM after administration of the last dose in the anesthetic test (cumulative, 320 mg/kg IP) across pretreatment groups. *, P < 0.05 compared with value for saline control group. HDK, high-dose ketamine (100 mg/kg); LDK, low-dose ketamine (32 mg/kg); SAL, saline.

Figure 3.

(A) Percentage of subjects in plane III anesthesia as a function of the cumulative ketamine dose. (B) Latency (h) to recovery (mean ± SEM after administration of the last dose in the anesthetic test (cumulative, 320 mg/kg IP) across pretreatment groups. HDC, high-dose cocaine (10 mg/kg); HDM, high-dose morphine (5.6 mg/kg); LDC, low-dose cocaine (3.2 mg/kg); LDM, low-dose morphine (1.8 mg/kg); SAL, saline.