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

Dagfinn A Matre1*, Luis Hernandez-Garcia4, Tuan D Tran5 and Kenneth L Casey23

Author Affiliations

1 Dept. of Work-related Musculoskeletal Disorders, National Institute of Occupational Health, Oslo, Norway

2 Dept. of Neurology, VA Medical Center, Ann Arbor, MI, USA

3 Dept. of Neurology, University of Michigan, Ann Arbor, MI, USA

4 Functional MRI Laboratory, University of Michigan, Ann Arbor, MI, USA

5 Dept. of Pediatrics, University of Medicine and Pharmacy of Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Molecular Pain 2010, 6:81  doi:10.1186/1744-8069-6-81

Published: 17 November 2010



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).


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.


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.