Neuroimaging Of Cold Allodynia Reveals A Central Disinhibition Mechanism Of Pain.

Allodynia refers to pain evoked by physiologically innocuous stimuli. It is a disabling symptom of neuropathic pain following a lesion within the peripheral or central nervous system. In fact, two different pathophysiological mechanisms of cold allodynia (ie, hypersensitivity to innocuous cold) have been proposed. The peripheral sensitization of nociceptive neurons can produce cold allodynia, which can be induced experimentally by a topical application of menthol. An alternative mechanism involves reduced inhibition of central pain processing by innocuous cold stimuli. A model to induce the latter type of allodynia is the conduction block of peripheral A-fiber input. In the presented study, functional MRI was used to analyze these two different experimental models of cold allodynia. In order to identify the underlying cerebral activation patterns of both mechanisms, the application of menthol and the induction of a mechanical A-fiber blockade were studied in healthy volunteers. The block-induced cold allodynia caused significantly stronger activation of the medial polymodal pain processing pathway, including left medial thalamus, anterior cingulate cortex, and medial prefrontal cortex. In contrast, menthol-induced cold allodynia caused significantly stronger activity of the left lateral thalamus as well as the primary and secondary somatosensory cortices, key structures of the lateral discriminative pathway of pain processing. Mean pain intensity did not differ between both forms of cold allodynia. Experimental cold allodynia is mediated in different cerebral areas depending on the underlying pathophysiology. The activity pattern associated with block-induced allodynia confirms a fundamental integration between painful and non-painful temperature sensation, ie, the cold-induced inhibition of cold pain.

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© 2019 Forstenpointner et al.

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RB, GW, AB and RM were supported by the German Federal Ministry of Education and Research (BMBF), German Research Foundation DFNS (grant 01 EM 0504) and an unrestricted educational grant from Pfizer, Germany. HS was supported by the BMBF (grant 01 GO 0511). AB reports grants and personal fees from Pfizer, personal fees from Grünenthal, Allergan and Munipharma, during the conduct of the study; honoraria from Astellas, Allergan, Bayer, Boehringer-Ingelheim, Grünenthal, and Pfizer; and he participated in advisory boards of Astellas, Boehringer-Ingelheim, Genzyme, and Grünenthal. RM reports grants and personal fees from Pfizer and personal fees from Grünenthal and Genzyme, during the conduct of the study. JF reports personal fees and non-financial support from Grünenthal GmbH and Sanofi Genzyme, personal fees from Bayer, non-financial support from Novartis, outside the submitted work. PH reports speaking fees from Pfizer and Genzyme; travel reimbursement from Grünenthal; and grants from BMBF and Medoc, outside the submitted work. MP, OG, GW, SW and OJ reports no conflicts of interest in this work. HRS has received honoraria from Novartis, Sanofi-Genzyme, Elsevier Publishers and Springer Publishing; reports grants from Lundbeckfonden, during the conduct of the study. HRS professorship is sponsored by Lundbeckfonden. RB reports personal fees from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuro-modulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD GmbH, Seqirus, Novartis, TAD Pharma GmbH, Allergan, Sanofi Pasteur, Medtronic, Bristol-Myers Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, Genentech, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene, Theranexus, Bayer AG, Akcea, and Asahi Kasei Pharma; grants from Pfizer, Genzyme GmbH, Grünenthal GmbH, Mundipharma, German Research Network on Neuropathic Pain (01EM0903), NoPain system biology (0316177C), German Research Foundation (DFG), EU-Project IMI Paincare, Novartis, German Federal Ministry of Education and Research (BMBF): member of the ERA_NET NEURON/IM-PAIN Project (01EW1503). Member of the EU Project No 633491: DOLORisk. Member of the IMI “Europain” collaboration and industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal GmbH, Eli Lilly and Boehringer Ingelheim Pharma GmbH&Co.KG.