Differential coding of hyperalgesia in the human brain: A functional MRI study

Abstract

Neuropathic pain can be both ongoing or stimulus-induced. Stimulus-induced pain, also known as hyperalgesia, can be differentiated into primary and secondary hyperalgesia. The former results from sensitization of peripheral nociceptive structures, the latter involves sensitization processes within the central nervous system (CNS). Hypersensitivity towards heat stimuli, i.e. thermal hyperalgesia, is a key feature of primary hyperalgesia, whereas secondary hyperalgesia is characterized by hypersensitivity towards mechanical (e.g. pin-prick) stimulation. Using functional magnetic resonance imaging (fMRI), we investigated if brain activation patterns associated with primary and secondary hyperalgesia might differ. Thermal and pin-prick hyperalgesia were induced on the left forearm in 12 healthy subjects by topical capsaicin (2.5%, 30 min) application. Equal pain intensities of both hyperalgesia types were applied during fMRI experiments, based on previous quantitative sensory testing. Simultaneously, subjects had to rate the unpleasantness of stimulus-related pain. Pin-prick hyperalgesia (i.e. subtraction of brain activations during pin-prick stimulation before and after capsaicin exposure) led to activations of primary and secondary somatosensory cortices (S1 and S2), associative-somatosensory cortices, insula and superior and inferior frontal cortices (SFC, IFC). Brain areas activated during thermal hyperalgesia (i.e. subtraction of brain activations during thermal stimulation before and after capsaicin exposure) were S1 and S2, insula, associative-somatosensory cortices, cingulate cortex (GC), SFC, middle frontal cortex (MFC) and IFC. When compared to pin-prick hyperalgesia, thermal hyperalgesia led to an increased activation of bilateral anterior insular cortices, MFC, GC (Brodmann area 24′ and 32′) and contralateral SFC and IFC, despite equal pain intensities. Interestingly, stronger activations of GC, contralateral MFC and anterior insula significantly correlated to higher ratings of the stimulus-related unpleasantness. We conclude that thermal and mechanical hyperalgesia produce substantially different brain activation patterns. This is linked to different psychophysical properties.

Introduction

The human pain experience is a complex sensation that is of paramount importance to maintain the body integrity and survival of human beings. It is a multidimensional phenomenon with sensory-discriminative, affective-motivational, motor and autonomic components (Treede et al., 1999). In the last decade, remarkable efforts have been undertaken to uncover the cortical processing of the human pain experience by non-invasive functional brain imaging techniques, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). These techniques provide evidence for an involvement of the thalamus, primary somatosensory cortex (S1), secondary somatosensory cortex (S2), insula, forebrain and cingulate cortex (gyrus cinguli; GC; for review, see Treede et al., 1999, Ingvar, 1999, Peyron et al., 2000). There is accumulating evidence that these areas process different aspects of pain (Rainville et al., 1997, Coghill et al., 1999, Hofbauer et al., 2001). In this context, it has been suggested that a medial pain system (e.g. GC and the forebrain) particularly encodes the affective-motivational pain aspects, whereas a lateral system (e.g. S1, S2) is likely to account for the sensory-discriminative pain dimension (Treede et al., 1999, Vogt BA and Sikes, 2000, Price, 2000, Sewards TV and Sewards, 2002). Basically, pain can be classified as nociceptive or neuropathic (Woolf and Mannion, 1999). Whereas most functional imaging studies were undertaken in healthy subjects during experimental nociceptive pain, only few investigations focused on the neural correlates of neuropathic pain syndromes (Hsieh et al., 1995, Peyron et al., 1998, Petrovic et al., 1999, Maihofner et al., 2003, Peyron et al., 2004, Maihofner et al., 2005). This type of chronic pain may result from damage to the peripheral or central nervous system (Woolf and Mannion, 1999). Neuropathic pain can be both ongoing or stimulus-induced (Koltzenburg et al., 1992, Ochoa JL and Yarnitsky, 1993). Stimulus-induced pain, also known as hyperalgesia, can be differentiated according to the kind of stimulation, such as chemical, thermal and mechanical. Following tissue injury, two types of hyperalgesias may develop. Primary hyperalgesia occurs at the site of tissue injury and is characterized by hyperalgesia to heat and tonic pressure. In contrast, secondary hyperalgesia clearly extends into uninjured tissue and is associated with increased pain in response to punctuate mechanical stimulation, i.e. pin-prick hyperalgesia (Koltzenburg et al., 1992), or pain elicited by gently stroking the skin, i.e. dynamic-mechanical allodynia (Ochoa and Yarnitsky, 1993). The underlying pathophysiology of primary and secondary hyperalgesia is substantially different as primary hyperalgesia results from sensitization of C-fibers in the periphery, whereas pin-prick hyperalgesia is maintained by sensitization of nociceptive pathways within the central nervous system (CNS) (Schmidt et al., 1995, Ziegler et al., 1999, Klede et al., 2003). Both types of hyperalgesia can also be provoked in healthy subjects following topical application of algogens, such as capsaicin and mustard oil (Koltzenburg et al., 1994, Kilo et al., 1994). Especially, application of capsaicin was demonstrated as a reliable and valid model to explore mechanisms of stimulus-evoked pain (Simone et al., 1989, Maihofner et al., 2004). In the present study, we used the capsaicin sensitization model in order to provoke primary and secondary hyperalgesia in healthy subjects. As the underlying pathophysiology of both hyperalgesias differs, we hypothesized that the corresponding brain processing may diverge as well. In order to investigate this hypothesis, we used fMRI to explore brain activations associated with the processing of primary and secondary hyperalgesia. Pin-prick and thermal hyperalgesia were provoked using topical capsaicin application. Equal pain intensities of both hyperalgesias were applied. We here report substantially different brain activation patterns during pin-prick and thermal hyperalgesia. This difference was linked to the perceived pain unpleasantness of the subjects.