Thomas J. Morrow

Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans

&NA; The purpose of the present study was to determine whether gender differences exist in the forebrain cerebral activation patterns of the brain during pain perception. Accordingly, positron emission tomography (PET) with intravenous injection of H2 15O was used to detect increases in regional cerebral blood flow (rCBF) in normal right‐handed male and female subjects as they discriminated differences in the intensity of innocuous and noxious heat stimuli applied to the left forearm. Each subject was instructed in magnitude estimation based on a scale for which 0 indicated ‘no heat sensation’; 7, ‘just barely painful’ and 10, ‘just barely tolerable’. Thermal stimuli were 40°C or 50°C heat, applied with a thermode as repetitive 5‐s contacts to the volar forearm. Both male and female subjects rated the 40°C stimuli as warm but not painful and the 50°C stimuli as painful but females rated the 50°C stimuli as significantly more intense than did the males (P=0.0052). Both genders showed a bilateral activation of premotor cortex in addition to the activation of a number of contralateral structures, including the posterior insula, anterior cingulate cortex and the cerebellar vermis, during heat pain. However, females had significantly greater activation of the contralateral prefrontal cortex when compared to the males by direct image subtraction. Volume of interest comparison (t‐statistic) also suggested greater activation of the contralateral insula and thalamus in the females (P<0.05). These pain‐related differences in brain activation may be attributed to gender, perceived pain intensity, or to both factors.

Variability of laser-evoked potentials: attention, arousal and lateralized differences

We recorded laser-evoked potentials (LEPs) from 20 normal subjects by stimulating the skin with pulses from an infrared CO2 laser. The conduction velocity of the peripheral afferent fibers mediating the LEPs averaged 14.9 m/sec. The amplitude of the LEP components correlated significantly with perceived stimulus intensity. During repetitive constant intensity stimulation, the peak-to-peak LEP amplitude decreased 38% during a distraction task and 42% during drowsiness and was absent during stage 2 sleep, indicating a modulation of responsiveness to laser stimulation during distraction and decreased states of arousal. Normative data revealed considerable intersubject variability in LEP latencies and amplitudes. Analysis of intrasubject lateralized (side-to-side) differences revealed that the relative peak-to-peak amplitude was less variable than that of the N or P components. For clinical applications using 3 S.D.s to define the normal range, a lateral interpeak amplitude difference greater than 28% would suggest focal or lateralized sensory abnormality in an individual patient. Vigilance and attentiveness to the stimuli should be monitored during the acquisition of LEPs.

A Unique Representation of Heat Allodynia in the Human Brain

Skin inflammation causes innocuous heat to become painful. This condition, called heat allodynia, is a common feature of pathological pain states. Here, we show that heat allodynia is functionally and neuroanatomically distinct from normal heat pain. We subtracted positron emission tomography scans obtained during painful heating of normal skin from scans during equally intense but normally innocuous heating of capsaicin-treated skin. This comparison reveals the specific activation of a medial thalamic pathway to the frontal lobe during heat allodynia. The results suggest that different central pathways mediate the intensity and certain qualitative aspects of pain. In making this differentiation, the brain recognizes unique physiological features of different painful conditions, thus permitting adaptive responses to different pain states.

Medial frontal cortex lesions selectively attenuate the hot plate response: possible nocifensive apraxia in the rat.

&NA; Lesions in the cingulate cortex have attenuated pain‐related behavior in humans. We wished to evaluate an animal model of this effect by studying the effects of bilateral lesions within the medial frontal cortex, including rat cingulate cortex, on performance in 3 behavioral tests: the formalin, hot‐plate, and tail‐flick tests. Average hot‐plate latencies, but not formalin test scores or tail‐flick latencies, were significantly increased by an average of 82% in rats with medial frontal cortex lesions, as compared to sham‐operated control rats. Motor function, as tested by righting and foot lifting responses and clinical observation, was not impaired. No effects were seen on hot‐plate latencies, tail‐flick latencies, and formalin pain scores in sham‐operated rats. These results suggest that the medial frontal cortex of the rat mediates certain types of supraspinally organized responses to noxious heat pain. Lesions that include the medial frontal and anterior cingulate cortex appear to disrupt the integration of increasing heat nociceptive input with motor responses that are necessary to execute quickly the escape behavior in the hot‐plate test.

Laser-evoked cerebral potentials and sensory function in patients with central pain.

&NA; Central pain syndromes (CPS) could be caused by disinhibition of spinothalamic excitability or by other central nervous system (CNS) changes caused by reduced spinothalamic function. To examine these possibilities, we studied 11 patients (ages 51–82 years) with unilateral central pain and with reproducible cerebral evoked vertex potentials in response to cutaneous stimulation of the normal side with pulses from an infra‐red CO2 laser. All patients had normal tactile and kinesthetic sensation; one had slightly decreased vibratory sense bilaterally. All showed, from the unaffected (asymptomatic) side, laser evoked potentials (LEPs) with negative (N) components ranging from 208 to 280 msec peak latency (av: 240 ± 6 SE msec) and peak amplitudes of 1–7 &mgr;V (av: 2.9 ± 0.5 SE &mgr;V), followed, in all but 1 patient, by positive (P) potentials ranging from 288 to 370 msec peak latency (av: 319 ± 7.7 SE msec) with peak amplitudes of 1–7 &mgr;V (2.8 ± 0.5 SE &mgr;V). Laser stimulation of the affected (symptomatic) side in 5 patients evoked LEPs with N‐P interpeak amplitudes that were within 20% of those evoked from the normal side. All but one of these patients had thresholds for warm, heat pain, and deep pain that were normal in comparison with the unaffected side. The excepted patient had the largest N‐P interpeak amplitude asymmetry (18.5%) of this group. Ratings of laser pulse intensity were either symmetrical (n = 2) or increased on the affected side (n = 3) in these patients. In contrast, laser stimulation of the affected side failed to evoke either N or P potentials in 6 patients, all of whom had lateralized increased thresholds for warm, heat pain, or deep pain, or reduced ratings of laser pulse sensation. Although 1 patient had increased ratings of laser pulse sensation, the amplitude of the LEP was always reduced on the side of increased pain or heat threshold in these CPS patients (Fisher exact test: P = 0.015). These results reflect primarily a deficit in spinothalamic tract function and do not suggest excessive CNS responses to synchronous activation of cutaneous heat nociceptors in patients with CPS.

Cocaine: evidence for supraspinal, dopamine-mediated, non-opiate analgesia

Cocaine (25 mg/kg i.p.) produces analgesia in the rat within 5 min and for a duration of 90 min as determined by the formalin test or for 30 min as determined by the hot plate test. Cocaine analgesia is unaffected by doses of naloxone that are sufficient to attenuate morphine analgesia in both tests. Chlorpromazine (3 mg/kg i.p.), SCH 23390 (100 micrograms/kg i.p.; a D1 dopamine receptor antagonist), and eticlopride (75 micrograms/kg i.p.; a D2 dopamine receptor antagonist) each attenuate cocaine analgesia in both tests at doses that alone do not affect performance in either test. Measurements of blood pressure and heart rate indicate that cocaine analgesia is not due to the activation of baroreceptor reflex afferents. We conclude that cocaine is a supraspinally acting, dopamine-mediated, non-opiate analgesic in the rat.

Topical capsaicin selectively attenuates heat pain and A δ fiber-mediated laser-evoked potentials

&NA; Cutaneous stimulation with CO2 laser pulses activates A &dgr; nociceptive afferents and evokes late cerebral potentials (LEPs), the amplitude of which correlates parametrically with the perceived magnitude estimation of laser pulses. Capsaicin is known to desensitize the nociceptive terminals of C fibers. In this double‐blind, vehicle‐controlled experiment, we tested the hypothesis that topical capsaicin would inactivate A &dgr; afferents and lead to an attenuation of the LEPs. Subjects applied capsaicin cream to the dorsum of one hand and vehicle cream to the other 3 times daily for a period of 5 weeks. At weekly intervals before starting, during administration and after discontinuation of capsaicin, LEPs were recorded and psychophysical thresholds and magnitude estimation for several sensory modalities were determined. The results of this study showed that topical capsaicin significantly and reversibly decreased the magnitude estimation of suprathreshold heat pain, laser pulses and amplitude of the LEPs. There was no statistically significant difference in light touch, deep pain and mechanical pain detection thresholds between the capsaicin‐ and vehicle‐treated hands. It indicated that topical capsaicin caused a definite functional and reversible inactivation of A &dgr; nociceptive afferent transmission. The decline in the magnitude estimation of laser pulses concomitantly with the attenuation of LEP amplitudes supports the hypothesis that some A &dgr; afferents mediate noxious heat in humans. These findings demonstrate the usefulness of LEP in the physiological evaluation of nociceptive pathways and its potential usefulness in objectively documenting the effect of pharmacological treatment on pain perception.

Cutaneous pain and detection thresholds to short CO2 laser pulses in humans: Evidence on afferent mechanisms and the influence of varying stimulus conditions

&NA; Pain and detection thresholds to short CO2 laser pulses were studied in healthy human subjects. Pain thresholds were significantly higher than detection thresholds in both hairy and glabrous skin; in the glabrous skin both thresholds were higher in the hairy skin. The range from detection threshold to pain threshold was larger in the glabrous skin. The minimal energy per surface area needed to produce any sensation (detection) or pain sensation decreased with increasing stimulus surface, and this spatial summation effect was to equal magnitude in the hairy and the glabrous skin. With decreasing stimulus pulse duration (from 45 to 15 msec) the detection and pain thresholds were elevated: this effect was stronger on pain thresholds. With increasing adapting skin temperature, less energy was needed to produce any sensation (detection) or pain sensation. The effect of adapting skin temperature was equal on pain and detection thresholds. The conduction velocity of fibers mediating laser evoked first sensations was in the thin fiber range (< 10 msec), according to a reaction time study. The results suggest that short CO2 laser pulses produce both non‐pain and pain sensations, but that both these sensations are based on the activation of the same primary afferent fiber population of slowly conducting nociceptive fibers. Central summation of primary afferent impulses is needed to elicit a liminal non‐painful sensation, and an increased number of impulses in the same fibers produces pain.

Long-term changes in behavior and regional cerebral blood flow associated with painful peripheral mononeuropathy in the rat

&NA; We identified long‐term (up to 12 weeks), bilateral changes in spontaneous and evoked pain behavior and baseline forebrain activity following a chronic constriction injury (CCI) of the sciatic nerve. The long‐term changes in basal forebrain activation following CCI were region‐specific and can be divided into forebrain structures that showed either: (1) no change, (2) an increase, or (3) a decrease in activity with regard to the short‐term (2 weeks) changes we previously reported. All the rats showed spontaneous pain behaviors that persisted throughout the 12‐week observation period, resembling the pattern of change found in four limbic system structures: the anterior dorsal thalamus, habenular complex, and the cingulate and retrosplenial cortices. In contrast, heat hyperalgesia was delayed in onset until 4 weeks following CCI, but then persisted, showing a nearly constant level of increased responsiveness. The forebrain activation that resembles this behavioral pattern of change is found in somatosensory cortex, and in the hypothalamic paraventricular nucleus and the basolateral amygdala. Finally, mechanical allodynia, which was maximal during the first 2 weeks following nerve injury and gradually recovered by the seventh post‐operative week uniquely matches the time course of changes in ventrolateral and ventroposterolateral thalamic activity. Our results indicate that peripheral nerve damage results in persistent changes in behavior and resting forebrain systems that modulate pain perception. The persistent abnormalities in the somatosensory cortex and thalamus suggest that the sensory thalamocortical axis is functionally deranged in certain chronic pain states.

Regional changes in forebrain activation during the early and late phase of formalin nociception: analysis using cerebral blood flow in the rat

&NA; This is the first neural imaging study to use regional cerebral blood flow (rCBF) in an animal model to identify the patterns of forebrain nociceptive processing that occur during the early and late phase of the formalin test. We measured normalized rCBF increases by an autoradiographic method using the radiotracer [99mTc]exametazime. Noxious formalin consistently produced detectable, well‐localized and typically bilateral increases in rCBF within multiple forebrain structures, as well as the interpeduncular nucleus (Activation Index, AI=66) and the midbrain periaqueductal gray (AI=20). Structures showing pain‐induced changes in rCBF included several forebrain regions considered part of the limbic system. The hindlimb region of somatosensory cortex was significantly activated (AI=31), and blood flow increases in VPL (AI=8.7) and the medial thalamus (AI=9.0) exhibited a tendency to be greater in the late phase as compared to the early phase of the formalin test. The spatial pattern and intensity of activation varied as a function of the time following the noxious formalin stimulus. The results highlight the important role of the limbic forebrain in the neural mechanisms of prolonged persistent pain and provide evidence for a forebrain network for pain.