THE CAPSAICIN MODEL TO EXPLORE PAIN SENSORY PROFILES AND FUNCTIONAL CONNECTIVITY IN HUMANS. A COMBINED PSYCHOPHYSICAL AND fMRI STUDY IN NORMAL CONTROLS.

Neuropathic pain is defined by the International Association for the Study of Pain as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system and it frequently may include allodynia and hyperalgesia. Animal models offer a large amount of experimental data, which are difficult to translate in the clinical setting. In contrast, the neurophysiological mechanisms underlying neuropathic pain in humans are not yet well understood and drugs are often ineffective. Given the pitfalls in translating animal data to humans, it is essential to have an experimental model of neuropathic pain in humans. Moreover there is a high variability in pain perception in humans and this may account for much of the variability in response to neuropathic pain drugs. The capsaicin model is used to explore sensory profiles in humans. Capsaicin is the pungent ingredient of chili peppers. Capsaicin allows the study of both gain-of-function (hyperalgesia and allodynia: similar to the chronic sensory symptoms of a patient with neuropathic pain) and loss-of-function (hypalgesia) phenomena. Capsaicin target is the transient receptor potential vanilloid 1 channel (TRPV1) which is expressed in the polymodal C and Aδ nociceptive fibers and it is a key molecolar component of the pain pathway. In the present study, we tested healthy human subjects in whom acute cutaneous pain is induced experimentally by topical application of high-concentration capsaicin (8%, patch) unlike other studies that used lower concentrations (0,025-3%). The first aim of this study was to investigate the variability of experimental pain perception in normal controls by studying somatosensory profiles before and during an experimental pain condition (8% capsaicin patch) using quantitative sensory testing (QST). Another aim was to investigate the changes and the connectivity in the resting state networks using BOLD functional magnetic resonance imaging before and during an experimental pain condition (8% capsaicin patch) in healthy subjects. We have combined the use of a psychophysical test applied peripherally in the skin stimulation site with a method of central nervous system imaging to explore the “pain pathway” from the peripheral receptors up to brain connections. In the first part of the study a standardized QST protocol was performed in a group of 32 normal volunteers prior to (T0) and after topical capsaicin application (3 x 3 cm, 30’) on the forearm (T1: early primary and secondary hyperalgesia/allodynia; T2: late hypalgesia). In the second experimental design, 18 healthy volunteers were submitted to a resting state fMRI protocol before and after capsacin path application to explore the Resting State Networks and functional connectivity, using FSL and CONN to process the data. Results of first experiment indicate that capsaicin affect both thermal and mechanical QST thresholds resulting in a pattern of “gain of function” with heat and pinprick hyperalgesia and dynamic mechanical allodynia. Results also showed different patterns of inter-individual variability with some more stable parameters than others. Regarding the second experiment we found greater and positive resting-state functional connectivity involving different brain areas in capsaicin condition compared to pre-capsaicin condition. We also found a reduced connectivity only for a couple of regions. This model might be useful to profiling novel analgesic agents in more limited numbers of subjects than required in patient efficacy studies.