Ketamine analgesia is not related to an opiate action in the periaqueductal gray region of the rat brain

Abstract

Ketamine is an injectable anesthetic agent that has been shown to interact as an agonist at opiate receptors. In addition, its antinociceptive action in rats is antagonized by the narcotic receptor antagonist naloxone. Thus it was assumed that the anesthetic may activate the pain inhibitory pathway, originating in the periaqueductal gray (PAG) and descending into the spinal cord, in a manner similar to that of narcotics like morphine. In the present study, it was verified that the systemic administration of naloxone (3 mg/kg i.p.) antagonized the elevation in tail-flick latency produced by an anesthetic dose of ketamine (160 mg/kg i.p.), but did not alter the duration of anesthesia (defined as duration of the loss of the righting reflex). However, when naloxone (3 μg/0.5 μl/30 sec) was given by microinjection into the PAG it was found to be ineffective against the ketamine-induced elevation of the tail-flick latency. In contrast, the microinjection of the antagonist significantly attenuated (halved) the elevated latency in response to systemically administered morphine (4 mg/kg s.c.). It was also shown that ketamine was unable to elicit an increase in the latency of the tail-flick reflex when administered directly into the PAG over a wide range (0.10–100 μg) of doses. On the other hand, a local anesthetic-like effect of ketamine, known to occur when the drug is used in high concentration, was observed when doses exceeding 0.1 μg were injected into the PAG. This action interfered with opiate actions in the PAG and made data from the microinjection studies difficult to interpret. The descending, pain inhibitory neuronal system originating in the PAG does not appear to participate in the antinociceptive action of ketamine measured by the tail-flick reflex. Perhaps the drug's effects are associated with alternative opiate mechanisms and/or opiate receptor subtypes not present on the cells of origin of the descending nerves within the PAG.