Pamela E. Paulson

Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats.

This experiment was designed to characterize the withdrawal syndrome produced by discontinuation of treatment with escalating, non-neurotoxic doses ofd-amphetamine (AMPH). AMPH withdrawal was associated with both transient and persistent changes in behavior and postmortem brain tissue catecholamine concentrations. During the first week of withdrawal rats showed a significant decrease in spontaneous nocturnal locomotor activity. This behavioral depression was most pronounced on the first 2 days after the discontinuation of AMPH pretreatment, was still evident after 1 week, but had dissipated by 4 weeks. Behavioral depression was not due to a simple motor deficit, because AMPH-pretreated animals showed a normal large increase in locomotion when the lights initially went out, but they did not sustain relatively high levels of locomotor activity throughout the night, or show the early morning rise in activity characteristic of controls. Behavioral depression was associated with a transient decrease in the concentration of norepinephrine (NE) in the hypothalamus, and a transient decrease in the ability of an AMPH challenge to alter dopamine (DA) concentrations in the caudateputamen and nucleus accumbens. AMPH pretreatment also produced persistent changes in brain and behavior. The persistent effects of AMPH were not evident in spontaneous locomotor activity, but were revealed by a subsequent challenge injection of AMPH. AMPH pretreated animals were markedly hyper-responsive to the stereotypy-producing effects of an AMPH challenge. This behavioral sensitization was not fully developed until 2 weeks after the discontinuation of AMPH pretreatment, but then persisted undiminished for at least 1 year. It is suggested that the transient changes in brain and behavior described here may represent an animal analogue of the “distress syndrome” seen in humans during AMPH withdrawal, which is associated with symptoms of depression and alterations in catecholamine function. On the other hand, persistent behavioral sensitization may be analogous to the enduring hypersensitivity to the psychotogenic effects of AMPH seen in former AMPH addicts.

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.

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.

Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis

The relationship between circadian changes in spontaneous motor activity in rats and dopamine (DA) neurotransmission in the dorsal or ventral striatum was assessed with on-line in vivo microdialysis. The concentration of DA and DA metabolites in the dorsolateral caudate nucleus increased significantly at night. In contrast, DA in the nucleus accumbens did not change significantly across the light-dark cycle. The concentration of DA metabolites in the nucleus accumbens did show circadian variation, however, which was comparable with that seen in the dorsolateral caudate nucleus. Although there was a significant positive correlation between the concentration of DA in both the dorsal and ventral striatum and spontaneous nocturnal motor activity, the relationship was very weak, especially for the accumbens. This suggest that regulating the level of spontaneous motor activity per se is not a primary function of the mesostriatal DA system.

Sensitization to systemic amphetamine produces an enhanced locomotor response to a subsequent intra-accumbens amphetamine challenge in rats.

Repeated amphetamine (AMPH) administration into the nucleus accumbens does not enhance (sensitize) the locomotor activity produced by a subsequent systemic AMPH challenge. We report here, however, that pretreatment with systemic injections of AMPH does produce a significant enhancement in the locomotor stimulant effects produced by intra-accumbens AMPH given 21 days after the last pretreatment injection of AMPH. These data support the hypothesis that neural adaptations in dopamine (DA) terminal fields are sufficient for theexpression of AMPH sensitization, although an action on DA cell bodies may be required for theinduction of AMPH sensitization.

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.

Regional Differences in the Effects of Amphetamine Withdrawal on Dopamine Dynamics in the Striatum: Analysis of Circadian Patterns Using Automated On-Line Microdialysis

The purpose of the study is to determine the relationship between behavioral symptoms of amphetamine withdrawal and the extracellular concentration of dopamine (DA) in the dorsolateral caudate nucleus and the nucleus accumbens across the entire light-dark cycle. This was accomplished using automated on-line microdialysis sampling in behaving rats. Animals were pretreated with escalating doses of d-amphetamine (or saline) over a 6-week period and then were withdrawn from amphetamine for 3, 7, or 28 days before testing. There were regional differences in the effects of amphetamine withdrawal on the concentrations of DA and DA metabolites in dialysate. Early during withdrawal (3 and 7 days), when animals showed postamphetamine withdrawal behavioral depression (nocturnal hypoactivity), there was a significant decrease in DA and DA metabolites in the dorsolateral caudate nucleus and a disruption in the normal circadian pattern of DA activity. In contrast, there was no effect of amphetamine withdrawal on DA dynamics in the nucleus accumbens. By 28 days after the discontinuation of amphetamine pretreatment, after basal DA in the caudate returned to normal, there was a significant increase in basal DA metabolism in both the caudate and the accumbens. This increase in DA metabolism may be related to the expression of sensitization, including a hypersensitivity to an amphetamine challenge. It is concluded that the role of the dorsal striatum in psychostimulant drug withdrawal syndromes deserves further consideration.

Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat

Abstract A unilateral chronic constriction injury (CCI) of the sciatic nerve produced bilateral effects in both pain related behaviors and in the pattern of forebrain activation. All CCI animals exhibited spontaneous pain‐related behaviors as well as bilateral hyperalgesia and allodynia after CCI. Further, we identified changes in baseline (unstimulated) forebrain activation patterns 2 weeks following CCI by measuring regional cerebral blood flow (rCBF). Compared to controls, CCI consistently produced detectable, well‐localized and typically bilateral increases in rCBF within multiple forebrain structures in unstimulated animals. For example, the hindlimb region of somatosensory cortex was significantly activated (22%) as well as multiple thalamc nuclei, including the ventral medial (8%), ventral posterior lateral (10%) and the posterior (9%) nuclear groups. In addition, several forebrain regions considered to be part of the limbic system showed pain‐induced changes in rCBF, including the anterior dorsal nucleus of the thalamus (23%), cingulate cortex (18%), retrosplenial cortex (30%), habenular complex (53%), interpeduncular nucleus (45%) and the paraventricular nucleus of the hypothalamus (30%). Our results suggest that bilateral somatosensory and limbic forebrain structures participate in the neural mechanisms of prolonged persistent pain produced by a unilateral injury.

Chronic, Selective Forebrain Responses to Excitotoxic Dorsal Horn Injury

Intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) results in excitotoxic injury which develops pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI) (R. P. Yezierski et al., 1998, Pain 75: 141-155; R. P. Yezierski et al., 1993, J. Neurotrauma 10: 445-456). Since spinal injury can lead to partial or complete deafferentation of ascending supraspinal structures, it is likely that secondary to the disruption of spinal pathways these regions could undergo significant reorganization. Recently, T. J. Morrow et al. (Pain 75: 355-365) showed that autoradiographic estimates of regional cerebral blood flow (rCBF) can be used to simultaneously identify alterations in the activation of multiple forebrain structures responsive to noxious formalin stimulation. Accordingly, we examined whether excitotoxic SCI produced alterations in the activation of supraspinal structures using rCBF as a marker of neuronal activity. Twenty-four to 41 days after unilateral injection of QUIS into the T12 to L3 spinal segments, we found significant increases in the activation of 7 of 22 supraspinal structures examined. As compared to controls, unstimulated SCI rats exhibited a significant bilateral increase in rCBF within the arcuate nucleus (ARC), the hindlimb region of S1 cortex (HL), parietal cortex (PAR), and the thalamic posterior (PO), ventral lateral (VL), ventral posterior lateral (VPL), and ventral posterior medial (VPM) nuclei. All structures showing significantly altered rCBF are associated with the processing of somatosensory information. These changes constitute remote responses to injury and suggest that widespread functional changes occur within cortical and subcortical regions following injury to the spinal cord.