Brief CommunicationBrainstem involvement in the initial response to pain
Introduction
Supraspinal processing of pain has been divided between processes in brainstem networks and in the cortex (Price, 2000). Although these systems are highly interactive, it has been postulated that they can be more or less involved in different phases of pain processing. While the brainstem seems to be more important in the immediate pain response, higher order regions seem to be more involved in the later response (Price, 2000).
However, the brainstem mediates a response to a complex situation, which may not just consist of pain. Instead, it is a way for the organism to rapidly cope in a life-threatening situation with a set of prepackaged behaviors to increase the chance for survival Bolles, 1970, Fanselow, 1994, Timberlake, 1993. These states have been described for experimental animals both in encounters with predators Blanchard et al., 1990, Fanselow and Sigmundi, 1986 but also elicited by noxious stimulation (Fanselow, 1982), for example, the dorsolateral periaqueductal grey (PAG) may independently of cortical networks increase autonomic responses, induce flight or fight behaviors, and nonopioid analgesia in direct response to noxious stimulation. Thus, it may be proposed that the dorsolateral PAG is involved in the initial response to noxious input that also includes an autonomic response (Fanselow, 1994).
It is unlikely that the dorsolateral PAG is the only brainstem region involved in this response. Several other brainstem nuclei, such as the parabrachial nucleus, the locus coeruleus, and the hypothalamus, also receive direct nociceptive information from the spinobulbar tract (Craig and Dostrovsky, 1999). These regions interact with a more elaborate brainstem network that may both modulate cortical and spinal processing Craig and Dostrovsky, 1999, Fields and Basbaum, 1999, Parvizi and Damasio, 2001.
The studies presented above are in line with the known relationship between acute pain and the sympathetic response on a behavioral level in human subjects Gracely, 1999, Jäning, 1995. The idea that the brainstem is more involved in the initial pain response may explain habituation of the autonomic responses during tonic pain (Lovallo, 1975) although the subjective pain ratings increase or remain equal Rainville et al., 1992, Tassorelli et al., 1995. Brain systems involved in the autonomic response during pain should therefore attenuate their activity during prolonged painful stimulation, while other regions participating in the processing of pain intensity and unpleasantness should increase in activity or at least remain equally activated during the prolonged pain. Thus, stimulus duration should have an opposite effect on brainstem vs. cortical activity during the processing of nociceptive signals. To test this hypothesis, we performed a PET study where we scanned different time components in prolonged painful cold stimulation and nonpainful cold stimulation. A rapid communication from the same data set on the S1 functional connectivity has previously been published (Petrovic et al., 2002b).
Section snippets
Experimental design
Seven subjects were included in the study (males, right handed, 20–35 years). No neurological or psychiatric illness was present according to the interviews. The study was approved by the ethical committee at the Karolinska Hospital.
Twelve measurements of the regional cerebral blood flow (rCBF) were made in each subject using a 3D Ecat Exact HR positron emission tomograph (PET) and bolus injections of 500 MBq [15O]butanol Berridge et al., 1990, Ingvar et al., 1994, Wienhard et al., 1994. The
Visual analogue scale
All subjects reported pain during all the noxious stimulations (pa and pb; average pain intensity rating = 53.2; SD = 18.7; 0 = no pain and 100 = highest imaginable pain intensity rated after each 2 min stimulation), and none of the subjects reported pain during the cold stimulations (ca and cb). Since the stimulation period continued for 2 min in both the conditions that were scanned during the first as well as the second minute, it was not possible to assess the pain ratings for the first and
Discussion
The main finding in this study showed that several regions in the brainstem were significantly more involved in the initial phase of the tonic painful stimulation as compared to the later phase (Fig. 3; Table 1). These rCBF effects were mirrored by a habituation in GSR, suggesting a habituation of sympathetic outflow (Fig. 1B). Since it has been shown that brainstem structures are involved in autonomic processing Loewy, 1990, Loewy, 1991, it seems reasonable to suppose that these regions may
Conclusion
This study showed significant effects of stimulus duration on the rCBF activity in brainstem areas encompassing the PAG, hypothalamus, and pons, as well as stimulus duration-dependent habituation of galvanic skin response. The rCBF changes due to stimulus duration were significantly more pronounced for pain as compared to cold in pons. The study also shows that the activity in the regions sensitive to stimulus duration had pain-specific functional relations with cortical areas involved in pain
Acknowledgements
We gratefully acknowledge the assistance of all members in the PET unit. Financial support was received from The Petrus and Augusta Hedlund Foundation, Swedish Research Councils (8246), and The Karolinska Institute.
References (54)
- et al.
Role of locus coeruleus in attention and behavioral flexibility
Biol. Psychiatry
(1999) - et al.
Tonic changes in alpha power during immersion of the hand in cold water
Electroenceph. Clin. Neurophysiol.
(1991) - et al.
Reward circuitry activation by noxious thermal stimuli
Neuron
(2001) - et al.
Subcortical structures involved in pain processing: evidence from single-trial fMRI
Pain
(2002) - et al.
The characterization and modelling of antipredator defensive behavior
Neurosci. Biobehav. Rev.
(1990) - et al.
Response plasticity of pain evoked reactions in man
Physiol. Behav.
(1982) - et al.
Neural activity in the human brain relating to uncertainty and arousal during anticipation
Neuron
(2001) Autonomic indices and reactive pain reports on the McGill pain questionnaire
Pain
(1982)Autonomic measures and behavioral indices of pain sensitivity
Pain
(1983)- et al.
Psychophysiological and modulatory interactions in neuroimaging
NeuroImage
(1997)
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
NeuroImage
Fear and anxiety: animal models and human cognitive psychophysiology
J. Affect. Disord.
Forebrain nuclei involved in autonomic control
Prog. Brain Res.
Consciousness and the brainstem
Cognition
Functional anatomy of arousal and attention systems in the human brain
Prog. Brain Res.
Pain-related cerebral activation is altered by a distracting cognitive task
Pain
A regression analysis study of the primary somatosensory cortex during pain
NeuroImage
Pupillary and cardiovascular responses to the cold-pressor test
J. Auton. Nerv. Syst.
A routine, automated synthesis of oxygen-15-labeled butanol for positron tomography
J. Nucl. Med.
Species-specific defence reactions and avoidance learning
Psychol. Rev.
Tickling expectations: neural processing in anticipation of a sensory stimulus
J. Cogn. Neurosci.
Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography
J. Neurophysiol.
Role of the cerebral cortex in autonomic functioning
Medulla to thalamus
Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans
J. Physiol.
Neural activity relating to generation and representation of galvanic skin conductance responses: a functional magnetic resonance imaging study
J. Neurosci.
Neuroanatomical basis for first- and second-order representations of bodily states
Nat. Neurosci.
Cited by (68)
Effects of neuromodulation on cognitive and emotional responses to psychosocial stressors in healthy humans
2023, Neurobiology of StressRevisiting the brain activity associated with innocuous and noxious cold exposure
2019, Neuroscience and Biobehavioral ReviewsSensitized brain response to acute pain in patients using prescription opiates for chronic pain: A pilot study
2019, Drug and Alcohol DependenceCitation Excerpt :Functional magnetic resonance imaging (fMRI) studies of acute pain in healthy individuals demonstrate that there is a reliable network of brain regions (the “Pain Matrix”) which are engaged by an acutely painful stimulus (Apkarian et al., 2005; Cauda et al., 2014; Tanasescu et al., 2016; Wager et al., 2013). These brain regions include: (1) the anterior cingulate cortex (ACC) and insula, which are primary nodes in the “Salience Network” (Seeley et al., 2007); (2) the somatosensory cortex and thalamus, which are primary sensory processing areas and their subcortical afferent; (3) as well as prefrontal regions and brainstem nuclei (Melzack, 2001; Petrovic et al., 2004). Positron emission tomography (PET) studies demonstrate that several of these areas have high endogenous opiate receptor levels, including the ACC (Vogt et al., 1995), insula (Baumgartner et al., 2006), and thalamus.
6-Methoxyflavanone attenuates mechanical allodynia and vulvodynia in the streptozotocin-induced diabetic neuropathic pain
2016, Biomedicine and PharmacotherapyCitation Excerpt :6-MeOF showed a KP ratio greater than 0.3, therefore, suggesting that it crosses not only the BBB, but also distributes extensively in the different brain areas implicated in the neuropathic pain. Brain stem is specifically involved in the initial supraspinal processing of pain signals and response to noxious stimulation [59]. The rostral ventromedial medulla (RVM) of the brain stem acts as an integral relay in the descending modulation of pain.
Psychophysiology of pain and opioid use: Implications for managing pain in patients with an opioid use disorder
2015, Drug and Alcohol DependenceCitation Excerpt :The subject indicates when he or she first feels pain (pain threshold), and then when the pain is no longer tolerable (pain tolerance). Autonomic sympathetic responses such as increased heart rate, blood pressure, galvanized skin response, and muscle tension are correlated to pain severity during the cold pressor test (Petrovic et al., 2004; Peckerman et al., 1994; Schachter, 1957; Schneiderman et al., 2000). Using the cold pressor test as a tonic pain model, Chen et al. (1989) divided 205 subjects into pain sensitive and pain tolerant groups based on length of time the subjects could tolerate the cold water, and examined several psychological factors correlated with pain sensitivity.
The Effect of the Cold Pressor Test on a Visually Evoked Cerebral Blood Flow Velocity Response
2012, Ultrasound in Medicine and BiologyCitation Excerpt :Previous studies with human subjects have shown that tonic pain decreases the excitability of the motor and somatosensory cortex (Rossi et al. 1998; Farina et al. 2001). Similarly, in a recent study CPT reduced visually-evoked potential (VEP) amplitudes and abolished normal VEP habituation in the occipital cortex (Coppola et al. 2010), which was suggested to be caused by the modulatory action of brainstem monoaminergic nuclei during tonic pain (Petrovic et al. 2004; Coppola et al. 2010). Consistent with the aforementioned studies, both noradrenergic and serotoninergic pathway stimulation has been found to have a general depressant effect on neuronal activity in various brain areas, including the visual cortex of cats and rats (Sato et al. 1989; Mantz et al. 1990; Follett and Gebhart 1992).