Animal models of chronic pain: scientific and ethical issues.
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Animal Experimentation↗
Biomedical subjects
Ronald Dubner
Publications and source records attributed to Ronald Dubner.
Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioral parameters and opioid receptor binding.
The stimulus specificity for enhancement of dynorphin gene expression in rat spinal cord was studied by combined measurements of the peptide dynorphin A 1-8 and preprodynorphin mRNA levels during peripheral inflammation induced by several agents. The density of kappa receptors, the putative receptor for dynorphin peptides, was examined using receptor binding with autoradiographic visualization. Mu and delta receptor classes were also studied. All inflammatory agents tested (carrageenan, phorbol ester, yeast and Freund's adjuvant) rapidly induced edema and thermal hyperalgesia. All agents also induced a rapid (within 8 h) elevation in dynorphin mRNA and, in comparison, a delayed (within 2 days) elevation of dynorphin A 1-8 peptide; peak peptide levels were reached at 4 days. No alteration of kappa, mu or delta receptor binding was observed at 4 h or 4 days post inflammation. The rapid development of thermal hyperalgesia and elevation of dynorphin mRNA and peptide content indicates that the involvement of dynorphin-containing neurons in nociceptive processing does not require a chronic abnormality and a dynamic picture of opioid modulation of sensory processing emerges. These data also demonstrate that activation of dynorphin biosynthesis in spinal cord is a feature common to hyperalgesia and peripheral inflammation and is not restricted to any one type of inflammatory agent. The lack of alteration in receptors suggests that the physiological effects of an increased biosynthesis are not accompanied by a concurrent down-regulation of opiate receptors.
Animals↗
The analgesic effect of amitriptyline on chronic facial pain.
The efficacy of amitriptyline was evaluated in 28 patients with chronic oral-facial pain. Most of the patients had evidence of musculoskeletal pain while some had a history suggesting pain of neurogenic origin. Two patients had mixed elements of neurogenic and musculoskeletal pain. Amitriptyline was more effective than placebo in reducing pain after 4 weeks of treatment. No effect was found after only 1 week of drug administration in either dose range. When the patients were divided into depressed and non-depressed groups based on their Hamilton depression scores, amitriptyline reduced pain in the depressed and in the non-depressed groups as compared to placebo. Amitriptyline reduced the depression scores in the depressed group but had no effect on the depression scores in the non-depressed group. Thus, pain reduction was not associated with a change in mood in the non-depressed group. Amitriptyline had no effect on patients' ratings of the intensity of experimental heat stimuli. We conclude that amitriptyline is effective in the treatment of chronic oral-facial pain and that its efficacy is independent of its effects on depression. It appears that tricyclic antidepressants act in a fashion different from opiate drugs that alter the sensory discriminative component of pain.
Adult↗
Future conduct of studies of chronic pain in animals.
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Animal Welfare↗
Reliability and validity of verbal descriptor scales of painfulness.
Previous studies have provided information about the reliability and validity of verbal descriptor scales of sensory intensity and unpleasantness and have shown that these two dimensions can be differentially affected by pharmacological manipulations. Since the relation between these dimensions and the general term 'pain' is not known, two experiments developed a verbal descriptor scale of painfulness and compared the sensitivity of this scale to pharmacological manipulations used previously with scales of sensory intensity and unpleasantness. In exp. I, 20 subjects used cross-modality matching to both handgrip force and tone duration to quantify the amount of pain implied by verbal descriptor phrases such as 'slightly painful,' 'somewhat painful' and 'very painful.' Ratio scales of relative magnitude for each individual were highly correlated within subjects (mean r = 0.92) and between a scale from each individual and a combined scale from others in the group (mean r = 0.93). These correlations indicate agreement between individual scales; an individual's scale values were predicted equally well by that individual or by a group of similar persons. In exp. II, 4 groups of 10 subjects rated the magnitude of painful tooth pulp sensations by choosing pain descriptors from randomized lists. Seven electrical stimuli spaced between individually determined pain threshold and tolerance values were delivered in random sequence 6 times before and after double-blind intravenous infusions of placebo, 0.11 mg/kg diazepam, 0.66 microgram/kg fentanyl or a combination of the diazepam and fentanyl doses. Mean responses were reduced significantly after all active drugs but not after placebo. These results suggest that the term pain does not represent a simple combination of sensory intensity and/or unpleasantness and shows that the sensitivity to an inert placebo, an active placebo, and an analgesic can vary with the type of pain assessment procedure.
Adolescent↗
Contrast medium causes the apparent increase in beta-endorphin levels in human cerebrospinal fluid following brain stimulation.
Levels of beta-endorphin immunoreactivity in cerebrospinal fluid were measured in 12 chronic pain patients undergoing the surgical implantation of an electrode into the periventricular gray matter. Cerebrospinal fluid fractions were collected following placement of a cannula into the third ventricle, following injection of metrizamide contrast medium into the ventricles, following implantation of the electrode, and following electrical stimulation. A second set of samples was collected on a non-surgical day before and after stimulation. Levels of beta-endorphin immunoreactivity increased significantly from baseline levels to post-electrode implantation in one group of patients, but no significant change was seen following the onset of stimulation. Immunoreactivity increased significantly following metrizamide injection in a second group and was still elevated, in comparison to baseline, following electrode placement, but no increase was seen following the onset of stimulation. Levels of immunoreactive beta-endorphin did not increase in either group after stimulation on a post-surgical day, despite consistent reports of pain relief. Addition of metrizamide or a related contrast medium, iothalamate meglumine (Conray) to the beta-endorphin radioimmunoassay revealed that both compounds interfered with antigen-antibody binding and also quenched the gamma radiation emitted by iodinated peptide ligands. Due to these combined effects, the contrast media alone produced results similar to those of the beta-endorphin standard. Moreover, similar observations were made when contrast media were incorporated into radioimmunoassays for met-enkephalin, dynorphin and cholecystokinin octapeptide. These findings indicate that increased levels of beta-endorphin in cerebrospinal fluid are not directly associated with patient report of pain relief following periventricular gray stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic Disease↗
Abnormal and collateral innervations of sympathetic and peripheral sensory fields associated with a case of causalgia.
A 41-year-old female developed spontaneous burning pain (causalgia) and stimulus-induced dysesthesia (allodynia) of the dorso-lateral part of her right foot following trauma. An L3 and L4 sympathectomy eliminated the spontaneous burning pain for only 1 year, but did not affect the stimulus-induced dysesthesia. We evaluated her two years post-sympathectomy with grouped sequential anesthetic blocks and sensory testing. Sympathetic blocks at L1 and L2 eliminated the burning pain and normalized heat perception from baseline hyperalgesia, indicating that the causalgia had been reactivated via more rostral sympathetic ganglia. Anesthetic block of the sural nerve eliminated both the burning pain and the stimulus-induced dysesthesia. During the sural nerve block, perception of touch and pin, but not heat, was preserved in the sural distribution. All perception was lost following subsequent block of the peroneal branches. When the peroneals were blocked first, perception of touch, pin and heat remained in the sural distribution. With peroneal block the burning pain was eliminated, but the stimulus-induced dysesthesia remained, even in the anesthetic peroneal territory. When sural block was added to the peroneal block the stimulus-induced dysesthesia was eliminated, and sensation in the sural distribution was lost. We conclude that the sural distribution received overalapping innervation for touch and pin-prick perception, but that heat perception, burning pain and the stimulus-induced dysesthesia were sural nerve dependent. Further, we were able to dissociate causalgia pain from allodynia in this patient.
Adult↗
Masseter inhibitory periods and sensations evoked by electrical tooth pulp stimulation.
The masseter inhibitory period and sensations evoked by electrical tooth pulp stimulation were assessed in 30 human subjects. Five intensities of electrical stimuli, producing sensations varying from below sensory detection threshold to suprathreshold pain, were applied to upper central incisors. At each stimulus intensity a train of 30, 1-msec, cathodal pulses with an interpulse interval of 2 sec was applied. The averaged masseter activity evoked by the 30 pulses at a fixed stimulus intensity was compared to the quality of the sensation elicited. The threshold for the masseter inhibitory period coincided approximately with an individual's detection threshold for the tooth pulp stimulation. Three configurations of masseter inhibitory periods (single, double and merged) were produced by different stimulus intensities. However, no particular configuration was associated unequivocally with pain sensation. Increases in stimulus intensity evoked changes both in the configuration of the masseter inhibitory period and in the quality of the sensation produced. Chi square analyses showed significant, but progressively weaker, associations between: (1) masseter inhibitory period configuration and stimulus intensity; (2) quality of sensation and stimulus intensity; and (3) quality of sensation and masseter inhibitory period configuration. The weakness of the association between the quality of sensation and masseter inhibitory period configuration also was demonstrated in a double-blind study of the effects of a narcotic analgesic, fentanyl. Although the strengths of non-pain and pain sensations were reduced significantly after fentanyl, there were no changes in the masseter inhibitory periods.
Adolescent↗
A validation model for verbal description scaling of human clinical pain.
Twenty-nine subjects used quantified verbal descriptors of sensory intensity (i.e., weak, mild, intense) or unpleasantness (i.e., annoying, unpleasant, distressing) to assess the intensity or unpleasantness of sensations evoked by painful electrical stimulation of the tooth pulp over a broad stimulus range, and by a natural thermal tooth pulp stimulus, cold spray applied to exposed dentin. In addition, subjects matched the intensity or unpleasantness of the sensations evoked by the natural stimulus to that of the electrical stimuli by both the Method of Limits and the Method of Constant Stimuli. Quantified verbal descriptor values of either the sensory intensity or unpleasantness of the electrical stimuli were linearly related to stimulus intensity on a log scale, indicating that the relationships can be described by power functions. The quantified verbal description of the natural thermal stimulus and the intensity of the electrical stimulus directly matched to the thermal stimulus determined the coordinates of the clinical stimulus data point. This point was close to the experimental stimulus power function, indicating that the verbal magnitude of the clinical stimulus is predicted by the verbal magnitude of the specific electrical stimulus intensity that was matched to the clinical stimulus. This consistency supports the validity of the use of quantified verbal descriptors for the assessment of both experimentally controlled noxious stimulation and uncontrolled clinical pain sensations. It also supports the validity of direct matches between clinical and experimental pain sensations and the unpleasantness of these sensations. This procedure provides a useful independent validational paradigm for clinical pain assessment.
Adolescent↗
Ratio scales of sensory and affective verbal pain descriptors.
The results of two experiments show that ratio scales of sensory and affective verbal pain descriptors are valid, reliable and objective. In the first experiment, 16 subjects rated 15 sensory and 15 affective verbal pain descriptors by numerical magnitude estimation and by cross-modality matching to handgrip force. Ratio scales of sensory and affective verbal pain descriptors computed for two separate groups were highly correlated between the groups (sensory, r = 0.97; affective, r = 0.98), as well as over session (r = 0.99, 0.98). Scales based on an individual's data correlated equally with either another set of scales from the same individual (r = 0.96, 0.98) or a mean scale from a similar group (r = 0.96, 0.89). Sensory and affective verbal descriptor scales from the first experiment correlated highly (r = 0.99, 0.99) with those from the second experiment in which 40 subjects rated verbal pain descriptors by cross-modality matching to time duration and to handgrip force. The ratio responses to the verbal descriptors in both experiments demonstrated specific functional relationships found for measurable psychophysical stimuli. This result supports the validity of cross-modality matched ratio scales of verbal stimuli. The reliability of these scales is shown by the high between-session, between-group and between-experiment correlations. The objectivity is shown by the similarity of within-subject and between-subject correlations for both group and individual descriptor scales.
Adolescent↗
Validity and sensitivity of ratio scales of sensory and affective verbal pain descriptors: manipulation of affect by diazepam.
The results of two experiments suggest that sensory and affective verbal descriptors provide a valid scaling method which discriminates between the sensory intensity and the affect, or unpleasantness, of electrocutaneous stimuli. Twenty-four subjects judged the sensory intensity and affect of noxious electrocutaneous stimuli by choosing verbal descriptors from randomized lists and by cross-modality matching to time duration and to handgrip force. The psychophysical functions for sensory intensity generated by the descriptor and the cross-modality functions for sensory intensity generated by the descriptor and the cross-modality methods are the same. Psychophysical functions for affect generated by thedescriptor and the cross-modality methods are different. However, only the descriptor method produces psychophysical functions for affect that are significantly different from all the sensory functions. This result suggest that only the descriptor method distinguishes between sensory intensity and affect. The discriminative power of the descriptor method is demonstrated further in an experiment in which 32 subjects rated either the sensory intensity or the affect of the electrocutaneous stimuli immediately before and after an i.v. administration of 5 mg diazepam. This common minor tranquilizer significantly lowered affective descriptor responses (P less than 0.005) without altering sensory descriptor and sensory and affective handgrip responses. These experiments indicate that sensory and affective verbal pain descriptors may be used as a valid and sensitive tool for the evaluation of pain and pain control methods.
Adolescent↗
Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.
Psychophysical experiments were carried out on 6 huma subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4-8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51-5% C). The magnitude of first and second pain sensations was estimated using cross-modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in Adelta and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of Adelta heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of singlt Adelta heat nociceptive afferents, C polymodal nociceptive afferents, and "warm" afferents of rhsus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (greater than 1/3 sec). These spinal cord summation mechanisms could account for the summation of second pain.
Adult↗
Neurons that subserve the sensory-discriminative aspects of pain.
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Animals↗