The introduction and current status of the multidimensional model of pain neurobiology.

Conceptual models are useful because they guide our practical actions related to whatever is represented by the model; this includes research that reveals the limitations of these actions and the potential for their improvement. These statements apply to many aspects of daily life and especially to pain as a challenge for both clinical practice specifically and neurobiology generally. In the first half of the 20th century, our conceptual model of pain, to the extent that it existed at all, was based on evidence supporting the proposition that pain emerged from activity within a very spatially limited set of central nervous system (CNS) structures located within the cerebral cortex and it's oligosynaptic connections with the thalamus. This CNS activity was strongly associated with the activation of physiologically distinct and specialized somatovisceral afferent fibers. All, or nearly all, aspects of the pain experience were thought to arise from, and be modified by, changes in that localized CNS activity. There was no compelling and widely accepted reason to consider an alternative model. However, neurophysiological, neuroanatomical, behavioral, and clinical evidence emerging in the late mid-20th century prompted a reconsideration of the prevailing model of pain neurobiology. Based on this new evidence and the perceived limitations of the prevailing model, pain could then be reasonably conceived as a multidimensional experience arising from the conjoint activation of physiologically and anatomically distinct but interacting CNS structures each separately mediating sensory discriminative, affective, and cognitive aspects of pain. This brief historical review describes the intellectual climate at the time this multidimensional model was proposed, the dispositions for resisting or accepting it, and concludes with a comment on the current status of the model as a fusion of distributed activations that create a unified perception of pain.

"First pain" in humans: convergent and specific forebrain responses.

BACKGROUND: Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI). RESULTS: Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers. CONCLUSIONS: These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.

Impact of chronic migraine attacks and their severity on the endogenous µ-opioid neurotransmission in the limbic system.

OBJECTIVE: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous µ-opioid neurotransmission. BACKGROUND: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. METHODS: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective µ-opioid receptor (µOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the µ-opioid receptor availability and the clinical data. RESULTS: µOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower µOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower µOR BPND values indicate either a decrease in µOR concentration or an increase in endogenous µ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in µOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R2 = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R2 = 0.08). CONCLUSIONS: Increased endogenous µ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous µ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

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.

Placebo-induced changes in spinal cord pain processing.

Pain is an essential sensory modality, signaling injury or threat of injury. Pain perception depends on both biological and psychological factors. However, it is not known whether psychological factors modify spinal mechanisms or if its effect is limited to cortical processing. Here, we use a placebo analgesic model to show that psychological factors affect human spinal nociceptive processes. Mechanical hyperalgesia (hypersensitivity) after an injury is attributable to sensitized sensory neurons in the spinal cord. After a 5 min, 46 degrees C heating of the skin, subjects developed areas of mechanical hyperalgesia. This area was smaller in a placebo condition compared with a baseline condition. This result suggests that placebo analgesia affects the spinal cord as well as supra-spinal pain mechanisms in humans and provides strong supporting evidence that placebo analgesia is not simply altered reporting behavior. Central sensitization is thought to mediate the exaggerated pain after innocuous sensory stimulation in several clinical pain conditions that follow trauma and nervous-system injury. These new data indicate that expectation about pain and analgesia is an important component of the cognitive control of central sensitization.

Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo.

OBJECTIVE: To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia. METHODS: We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase. RESULTS: Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge. CONCLUSIONS: Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release.

Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis.

The human palm has a lower heat detection threshold and a higher heat pain threshold than hairy skin. Neurophysiological studies of monkeys suggest that glabrous skin has fewer low threshold heat nociceptors (AMH type 2) than hairy skin. Accordingly, we used a temperature-controlled contact heat evoked potential (CHEP) stimulator to excite selectively heat receptors with C fibers or Adelta-innervated AMH type 2 receptors in humans. On the dorsal hand, 51 degrees C stimulation produced painful pinprick sensations and 41 degrees C stimuli evoked warmth. On the glabrous thenar, 41 degrees C stimulation produced mild warmth and 51 degrees C evoked strong but painless heat sensations. We used CHEP responses to estimate the conduction velocities (CV) of peripheral fibers mediating these sensations. On hairy skin, 41 degrees C stimuli evoked an ultra-late potential (mean, SD; N wave latency: 455 (118) ms) mediated by C fibers (CV by regression analysis: 1.28 m/s, N=15) whereas 51 degrees C stimuli evoked a late potential (N latency: 267 (33) ms) mediated by Adelta afferents (CV by within-subject analysis: 12.9 m/s, N=6). In contrast, thenar responses to 41 and 51 degrees C were mediated by C fibers (average N wave latencies 485 (100) and 433 (73) ms, respectively; CVs 0.95-1.35 m/s by regression analysis, N=15; average CV=1.7 (0.41) m/s calculated from distal glabrous and proximal hairy skin stimulation, N=6). The exploratory range of the human and monkey palm is enhanced by the abundance of low threshold, C-innervated heat receptors and the paucity of low threshold AMH type 2 heat nociceptors.

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

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 (less than 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.

Responses of single cutaneous fibers to noxious thermal pulse stimulation of cat upper hind limb.

Previous experiments have shown that cats respond to noxious thermal pulse stimulation of the upper hind limb at an average latency of 2.3 sec. To determine if C fiber afferents could mediate this response, we recorded the response latency and threshold of single fibers of cat femoral cutaneous nerve to the same stimuli used in the behavioral experiments. Of 28 C fibers tested, 10 (36%) responded to heating; 4 (17%) of 24 fibers with conduction velocities of 2.5-30 m/sec responded to heat. All fibers but one discharged within 1.0 sec of thermal pulse onset (median: 800 msec) at an average and median threshold of 46 degrees C. Thermal nociceptors with C fiber afferents could mediate the initiation of behavioral nocifensive responses to heat in the cat.

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

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.

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

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.

Central delay of the laser-activated rat tail-flick reflex.

The latency of the heat-activated rat tail-flick (TF) reflex is dependent upon 4 variables, none of which has previously been determined: activation of cutaneous nociceptors (TN); afferent conduction to the dorsal horn (TA); conduction within the central nervous system (CNS) (central delay); and conduction from the ventral horn (VH) to, and activation of, tail muscles (TE). Using a CO2 infrared laser (10 W, 45 msec) to produce synchronous activation of tail-skin nociceptors, TF latency (EMG response) was measured in 10 awake rats. Based on shifts in response latency from points of stimulation near the tip and base of the tail, conduction velocity in the afferent limb of the reflex was estimated to be 0.76 +/- 0.11 m/sec. This indicates that the response is mediated by C fibers. The rats were then anesthetized with pentobarbital and multiple-unit activity and evoked potentials (EPs) were recorded from the superficial dorsal horn at spinal segments S3-CO1 during laser or high-intensity electrical (10 mA, 1 msec) stimulation of the tail. Unit activity and EPs elicited by both stimuli consisted of two distinct components, corresponding to activation of A and C fibers. The difference in latency between laser and electrical evoked activity indicated that 60.00 +/- 7.33 msec was required for activation of nociceptors by the laser. Electrical stimulation of the VH at S3-CO1 in 3 rats produced a TF (EMG) response in 4 msec. Central delay, calculated as total TF time minus (TN+TA+TE), was 82.3 +/- 13.08 msec. This represents the time frame during which modulation of the reflex by an intrinsic, pain-activated, supraspinal system could occur.

Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing.

Recent studies have demonstrated that persons with fibromyalgia display abnormal processing of different types of painful stimulation, suggesting the disorder is characterized by a central pain-processing deficit not limited specifically to muscle pain. In the present study, 20 women with fibromyalgia and 20 normal, healthy women were compared on measures of pressure pain stimulation and response to contact thermal heat at both noxious and innocuous intensities. Women with fibromyalgia displayed significantly lower pressure pain thresholds at 18 tender point locations as defined by the American College of Rheumatology criteria, as well as lower pressure pain thresholds at five control sites. Women with fibromyalgia had significantly lower heat pain thresholds and tolerances when stimulated on the volar surface of the left forearm. When examining visual analog ratings of intensity and unpleasantness to constant stimuli, a multivariate analysis of variance performed on these ratings indicated that there were significant main effects of level of stimulation and group. Individual analysis of variances at each temperature revealed significant differences between the groups in pain intensity and unpleasantness ratings at both noxious and innocuous temperatures. Multiple regression analyses indicated that greater pain catastrophizing and diagnosis of fibromyalgia were associated with decreased pain thresholds and tolerances in the entire sample, whereas, self-report of depressive symptoms was associated with increased thresholds and tolerances. Self-report of somatic symptoms was not associated with these measures. These findings indicate that persons with fibromyalgia display altered perception of both pressure and thermal stimulation, even at innocuous levels. They also suggest that catastrophic thoughts about pain may play a role in increased pain perception in this population.

Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons.

Patients with central pain (CP) typically have chronic pain within an area of reduced pain and temperature sensation, suggesting an impairment of endogenous pain modulation mechanisms. We tested the hypothesis that some brain structures normally activated by cutaneous heat stimulation would be hyperresponsive among patients with CP but not among patients with a central nervous system lesion causing a loss of heat or nociceptive sensation with no pain (NP). We used H(2)(15)O positron emission tomography to measure, in 15 healthy control participants, 10 NP patients, and 10 CP patients, increases in regional cerebral blood flow among volumes of interest (VOI) from the resting (no stimulus) condition during bilateral contact heat stimulation at heat detection, heat pain threshold, and heat pain tolerance levels. Both patient groups had a reduced perception of heat intensity and unpleasantness on the clinically affected side and a bilateral impairment of heat detection. Compared with the HC group, both NP and CP patients had more hyperactive and hypoactive VOI in the resting state and more hyperresponsive and hyporesponsive VOI during heat stimulation. Compared with NP patients, CP patients had more hyperresponsive VOI in the intralaminar thalamus and sensory-motor cortex during heat stimulation. Our results show that focal CNS lesions produce bilateral sensory deficits and widespread changes in the nociceptive excitability of the brain. The increased nociceptive excitability within the intralaminar thalamus and sensory-motor cortex of our sample of CP patients suggests an underlying pathophysiology for the pain in some central pain syndromes.

Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation.

Noxious cutaneous contact heat stimuli (48 degrees C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.

C-fiber-related EEG-oscillations induced by laser radiant heat stimulation of capsaicin-treated skin.

Nociceptive input reaches the brain via two different types of nerve fibers, moderately fast A-delta and slowly conducting C-fibers, respectively. To explore their distinct roles in normal and inflammatory pain we used laser stimulation of normal and capsaicin treated skin at proximal and distal arm sites in combination with time frequency transformation of electroencephalography (EEG) data. Comparison of phase-locked (evoked) and non-phase-locked (total) EEG to laser stimuli revealed three significant pain-related oscillatory responses. First, an evoked response in the delta-theta band, mediated by A-fibers, was reduced by topical capsaicin treatment. Second, a decrease of total power in the alpha-to-gamma band reflected both an A- and C-nociceptor-mediated response with only the latter being reduced by capsaicin treatment. Finally, an enhancement of total power in the upper beta band was mediated exclusively by C-nociceptors and appeared strongly augmented by capsaicin treatment. These findings suggest that phase-locking of brain activity to stimulus onset is a critical feature of A-delta nociceptive input, allowing rapid orientation to salient and potentially threatening events. In contrast, the subsequent C-nociceptive input exhibits clearly less phase coupling to the stimulus. It may primarily signal the tissue status allowing more long-term behavioral adaptations during ongoing inflammatory events that accompany tissue damage.