Stephen Miksic

Tolerance to morphine-produced discriminative stimuli and analgesia

Male hooded rats were trained in Skinner boxes to press one lever after a morphine injection (10 mg/kg) and another lever after a saline injection (1 ml/kg) on an FR 10 schedule of food reinforcement. After the drug discrimination was well established, the rats were tested for stimulus generalization at different doses of morphine, followed by assessment of tail withdrawal latency as a measure of analgesia. Subjects were then administered increasing doses of morphine sulphate to induce and increased level of tolerance. New dose-response curves indicated that tolerance developed to the morphine-induced discriminative stimulus, and to the analgesic action of morphine, but doses of morphine that failed to cause detectable analgesia still produced a pronounced discriminative stimulus.

Acquisition and Extinction of a Conditioned Hyperthermic Response to a Tone Paired with Morphine Administration

Following a 7-day baseline period, five male hooded rats were injected daily with a constant dose (20 mg/kg) of morphine sulfate. Immediately following the injections they were taken to a sound-attenuated room and exposed to a 5,000 cps tone for 90 min. On certain predetermined days of the morphine treatment, rectal temperatures were measured before each injection and 30 min following the onset of the tone. Also, after the 11th, 19th, and 57th morphine-tone pairing, the rectal temperatures were measured before and after a saline injection which was paired with tone. On these days tone presentations by themselves were sufficient to cause a reliable increase in rectal temperature resembling that seen following an injection of morphine. When tone presentations were continued, without further pairing with morphine, the hyperthermic response to the tone was gradually extinguished. However, a significant increase in rectal temperature in response to the tone was again observed following a second set of five morphine-tone pairings.

Discriminable Stimuli Produced by Analgesics

Narcotic analgesics are drugs primarily used to relieve pain. Although narcotic drugs were originally natural products, many new drugs are synthetic. All known narcotic analgesics also produce a number of effects other than analgesia which make them valuable for other clinical uses but also constitute potentials for abuse and narcotic dependence. In addition, there are several pharmacological properties which are characteristic of only a few narcotics and are absent in the rest of them. For example, morphine is known to initially cause vomiting and later show a strong anti-emetic property. All synthetic narcotics are purely anti-emetic and are devoid of the initial emetic action. Similarly, various narcotic analgesics differ in their respiratory depressant property. Whereas they all produce respiratory depression, with some a rapid tolerance develops which allows for further use to relieve pain without concommitant depression of respiration.

Discriminative stimulus properties of desipramine

In an operant procedure of lever pressing on a FR10 schedule of food reinforcement, male hooded rats were trained to respond on a lever on one side of a food cup following a desipramine (10 mg/kg) injection and to respond on a lever on the other side following a saline injection. Sixty percent of the rats learned to reliably discriminate desipramine from saline. The rate of lever pressing at this dose of desipramine was 49% of the saline response rate. No tolerance to this depressant effect was observed after 20 injections. Subjects selected the appropriate desipramine lever 91, 29 and 18% of the time following 10, 2.5 and 0 (saline) mg/kg of desipramine. Imipramine and protryptyline each produced 50% selection of the desipramine lever at a dose of 40 mg/kg. Lower doses were less effective. d-Amphetamine produced 20 and 67% desipramine lever selection at 0.64 and 1.25 mg/kg respectively.

Lack of tolerance development to benzodiazepines in antagonism of the pentylenetetrazol discriminative stimulus

In an operant procedure of lever pressing on FR 10 schedule of food reinforcement male hooded rats were trained to respond on a lever on one side of a food cup following a 20 mg/kg pentylenetetrazol (PTZ) injection and to respond on a lever on the alternate side following a 1 ml/kg saline injection. Upon acquisition of the PTZ-saline discrimination, diazepam and chlordiazepoxide were tested and found to antagonize the PTZ discriminative stimulus. The animals were then injected with 10 mg/kg diazepam or chlordiazepoxide for ten consecutive days. New dose-response curves obtained following this treatment indicated that tolerance did not develop to the antagonism of the PTZ discriminative stimulus by these benzodiazepines.

Generalization study with some narcotic and nonnarcotic durgs in rats trained for morphine-saline discrimination

Rats were trained to lever-press on an FR-10 schedule for food reinforcement, and to respond differentially on two levers while discriminating the effects of morphine (10 mg/kg) injection from those of saline (1 ml/kg). Following discrimination training, the morphine stimulus was generalized to propoxyphene, methadone, fentanyl, and sulfentanyl in a dose-dependent manner, and saline was generalized to alcohol, pentobarbital, azaperone, clonidine, naloxone, and pchloroamphetamine. p-Chloroamphetamine failed to block the morphine stimulus.

Discriminative response control by naloxone in morphine pretreated rats.

In an operant procedure using a lever press response 12 male, hooded rats were trained to discriminate 1.25 mg/kg naloxone from a saline injection. On certain days, according to a counterbalanced training schedule, naloxone was administered 8 h after 40 mg/kg morphine and 10 min prior to a trial in which food was available on an FR10 schedule from one of two levers in a dual lever operant chamber. On other days saline was administered 10 min prior to a trial in which food was made available by pressing the other lever. After criterion performance for acquisition of the discrimination had been reached, tests were carried out to determine its nature. Discrimination of naloxone was dose-dependent and was significantly diminished when naloxone was administered 36 h after morphine. Partial generalization of cyclazocine with naloxone was observed. Spontaneous withdrawal from morphine, tested during trials preceeded by an injection of saline instead of naloxone at various time intervals after morphine, did not generalize with the naloxone discriminative stimulus.

Alleviation of narcotic withdrawal syndrome by conditional stimuli

We systematically paired auditory, olfactory, and social stimuli with each injection of morphine in rats. We found that, when morphine was kept constant at a low dose, the external stimuli acquired the property of a conditional stimulus (CS) to cause hyperthermia which was antagonized by naloxone. In rats in which morphine doses were regularly increased to cause morphine dependence, the CS presented during withdrawal, caused reduction in withdrawal signs (wet shakes, hypothermia, aggression) and produced hyperglycemia as well as elevation of striatal homovanillic acid. CS-induced alleviation of withdrawal hypothermia was blocked by mecamylamine, phenoxybenzamine, haloperidol, benztropine or naloxone but not by cyproheptadine or propranolol.

Reduction of morphine-withdrawal aggression by conditional social stimuli

Sixty male hooded rats were made physically dependent on morphine by steadily increasing doses of morphine sulphate. A maintenance dose of 400 mg/kg/day was reached in 10 days and was continued for 5 additional days. At the end of the 15-day period all rats were withdrawn for 72 h and aggressive responses (attacks, rearing, and vocalization) were recorded for a 60-min period. One treatment group, in which a social experience had been paired with each morphine injection, showed significantly less morphine-withdrawal aggression than rats in two other groups which either remained socially isolated throughout the addiction period, or were grouped both at the time of morphine injection and during between-injection intervals.

DISCRIMINATION OF THE INTEROCEPTIVE STIMULI PRODUCED BY PHENYL-QUINONE. A MEASURE OF THE AFFECTIVE COMPONENT OF PAIN IN THE RAT

Hooded rats were presented with a food reinforced (FRIO) two choice operant task. Injections of the irritant/writhe-inducing agent Phenyl-p-benzoquinone (PBQ) served as a discriminative stimulus for availability of food at one lever, while absence of PBQ signalled availability of reinforcement at the other. Subsequent tests demonstrated that the PBQ discrimination was antagonized in a dose-dependent manner by IP injections of morphine sulphate (ED50 4 mg/kg) and to a less extent by acetysalicylic acid (PO). These results suggest that operant discrimination of aversive stimuli can be used to measure the subjective component of pain in animals, and determine the capacity of drug treatments to alleviate pain.