Measurement of pain and morphine hypalgesia in monkeys

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Abstract
In order to determine the relative sensitivities of different behaviors to systemic morphine, monkeys were trained: (a) to escape electrical stimulation (ES) at intensities that defined escape thresholds and permitted quantification of reactions to sub- and suprathreshold stimuli, (b) to perform the same operant response to auditory stimulation for food reinforcement, and (c) to detect minimal intensities of light tactile stimulation, defining thresholds for touch. Thresholds for escape responses corresponded to pain thresholds of human subjects previously tested with identical stimulus parameters. The response measures that best differentiated suprathreshold levels of stimulation of the hind limbs were the force and the speed of escape responses by the forelimbs. Reflexive responses of the stimulated leg were related to ES intensity by a negatively accelerating function that was flat through much of the range of stimulus intensities that were escaped. Frequency histograms of adjunctive behaviors in the intertrial intervals revealed little, if any, relationship to the presence or the intensity of ES. The frequencies of intertrial vocalizations, spontaneous bar pulls and general bodily activity were similarly distributed following subthreshold vs. suprathreshold levels of ES and following ES vs. food reinforced trials. Dose-response curves for the different behavioral measures revealed significant effects of systemic morphine at the following dosages: (a) The adjunctive behaviors clearly were the most susceptible to depression. Intertrial vocalizations, bar pulls and activity were reduced significantly in frequency at 0.25 mg/kg and above. (b) At doses of 1 mg/kg and above, the percentage, speed and force of escape responses were reduced. The effects on response tendency and latency cannot be ascribed with confidence to an inhibition of pain, since the percentage and speed of responses for food reinforcement also were reduced at these dosages; and thresholds for detection of light touch were significantly elevated. The force of appetitive responses was not significantly reduced by moderate doses of morphine, suggesting that reduction of escape force may represent an effect on pain sensitivity. (c) The magnitudes of reflexive responses to ES were increased by doses below 3 mg/kg, and 3-5 mg/kg attenuated reflexive force. The low doses appeared to release an inhibition of reflexive vigor that could be demonstrated by behavioral disruption prior to ES. At the doses that depressed reflex reactions, the animals gave evidence of a powerful behavioral suppression that virtually eliminated adjunctive responses and reduced the frequency, speed and vigor of operant responses to non-nociceptive or nociceptive stimulation. These results document a requirement of high levels of systemic morphine to attenuate reactions to phasic pain from activation of myelinated peripheral afferents. At the doses that are commonly used to evaluate reactions of laboratory animals to somatosensory stimuli, rigorous control procedures are required to factor out generalized behavioral suppression.