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.

Vital Sign Changes During Intravenous Ketamine Infusions for Depression

“…It is well known that repeated ketamine use leads to physiological tolerance in the context of its anesthetic properties. 37 However, it is not well studied whether cardiovascular response, nor reduction in depressive symptoms, are subject to increasing dose requirements for the same physiological or psychological impact. Although in the current study average change in systolic blood pressure gradually declined with each subsequence infusion for responders, there seemed to be no coherent pattern to average blood pressure response for subsequent infusions in non-responders.…”

An Update of Ketamine Illicit Use

“…Other papers demonstrate animals chronically given ketamine that required increased doses of ketamine to reach the target anesthetic plane. Moreover, animals had a shorter duration of anesthesia [86,88]. Surprisingly, rats pretreated with intraperitoneal morphine at a dose of 5.6 mg/kg demonstrated cross-tolerance to ketamine's anesthetic effects [88].…”

“…Moreover, animals had a shorter duration of anesthesia [86,88]. Surprisingly, rats pretreated with intraperitoneal morphine at a dose of 5.6 mg/kg demonstrated cross-tolerance to ketamine's anesthetic effects [88].…”

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

“…The reasons for these mixed outcomes are unclear and might include higher treatment resistance levels 58 , chronic history of depression 58 , ineffective dosing, and possible tolerance-like phenomena 55,58,59 . For example, Sprague-Dawley rats develop tolerance to repeated administration of anesthetic doses of ketamine, possibly arising as a result of receptor desensitization, reduction of receptor density, or increased induction of metabolizing enzymes 60 . Also, a recent animal study comparing the effects of a single and repeated treatment of ketamine demonstrated the lack of antidepressant-like effectiveness of long-term administration 61 , hypothesizing to result from the detrimental effects of the parvalbumin interneurons loss in the prefrontal cortex after repeated treatment 62 and/or possible metabolic side effects.…”