INVITED REVIEW Cytokine Modulation is Necessary for Efficacious Treatment of Experimental Neuropathic Pain Paola Sacerdote & Silvia Franchi & Sarah Moretti & Mara Castelli & Patrizia Procacci & Valerio Magnaghi & Alberto E. Panerai Received: 27 September 2012 / Accepted: 4 December 2012 / Published online: 16 December 2012 # Springer Science+Business Media New York 2012 Abstract Neuropathic pain originates from a damage or disease affecting the somatosensory system. Its treatment is unsatisfactory as it appears refractory to most analgesics. Animal models of neuropathic pain are now available that help to clarify the underlying mechanisms. Recently it has been recognized that inflammatory and immune mecha- nisms in the peripheral and in the central nervous system play a role in the onset and the maintenance of pain. In response to nervous tissue damage, activation of resident or recruited immune cells leads to the production of inflamma- tory mediators, as cytokines. In models of neuropathic pain, such as nerve injury and diabetes induced neuropathy, the time course of the expression of the proinflammatory cyto- kines TNF-α,IL-1β and IL-6 and of the antiinflammatory cytokine IL-10 has been well characterized both in the peripheral (sciatic nerve, dorsal root ganglia) and the central (spinal cord) nervous system. These cytokines appear acti- vated/modulated in the nervous tissue in parallel with the occurrence of painful behaviour, i.e. allodynia and hyper- algesia. Novel therapeutic approaches efficacious to reduce painful symptoms, for example treatments with the non specific purinergic antagonist PPADS, the phytoestrogen genistein and a cell stem therapy with murine adult neural stem cells also re-established a balance between pro and antinflammatory mediators in the peripheral and central nervous system. These data suggest a pivotal role of immune system and inflammation in neuropathic pain. The modulation of inflammatory molecules appears to be a common trait accomplished throughout different mecha- nisms by different drugs that might converge in neuropathic pain modulation. Keywords ATP . Cytokines . Genistein . Neuroinflammation . Neuropathic pain . Stem cells Introduction Pain usually arises as a consequence of activation of primary nociceptive afferents by actually or potentially tissue- damaging stimuli and processing of this activity within the nociceptive system. The pain deriving is an early warning physiological protective response, essential to detect and min- imize contact with damaging or noxious stimuli (Woolf 2010). Pain however, may also arise from activity generated within the nervous system, without adequate stimulation of periph- eral sensory neurons. This pathological pain, which is not a symptom of some disorder but rather a disease state of the nervous system, can occur after damage of the nervous sys- tem: this is neuropathic pain. The current definition of neuro- pathic pain useful for both clinical and research purposes is “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” (Treede et al. 2008). Neuropathic pain arises from lesions to both the central and peripheral nervous system and in the human many etiologies have been recognized: a partial list is given in Table 1. Distinct symptoms of neuropathic pain may classically include both gain of function, such as allodynia (pain resulting from stimuli that are normally innocuous) and the presence of spontaneous pain, or loss of function, such as hypoaesthesia (Treede et al. 2008; Zimmermann 2001; Colleoni and Sacerdote 2010). Mechanical and thermal hyperalgesia P. Sacerdote (*) : S. Franchi : S. Moretti : M. Castelli : V. Magnaghi : A. E. Panerai Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy e-mail: paola.sacerdote@unimi.it P. Procacci Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy J Neuroimmune Pharmacol (2013) 8:202–211 DOI 10.1007/s11481-012-9428-2