RAPID REPORT ANTI-ALLODYNIC EFFICACY OF BOTULINUM NEUROTOXIN A IN A MODEL OF NEUROPATHIC PAIN S. LUVISETTO, S. MARINELLI, S. COBIANCHI AND F. PAVONE* CNR Institute of Neuroscience, Psychobiology and Psychopharmacol- ogy, Via del Fosso di Fiorano 64, I-00143 Roma, Italy Abstract—Neuropathic pain is typified by injuries to the pe- ripheral and central nervous system and derives from such causes as cancer, diabetes, multiple sclerosis, post-herpetic neuralgia, physical trauma or surgery, and many others. Pa- tients suffering neuropathic pain do not respond to conven- tional treatment with non-steroidal anti-inflammatory drugs and show a reduced sensitivity to opiates often associated with serious side effects. Recently, it has been demonstrated that botulinum neurotoxin serotype-A (BoNT/A) is able to induce analgesia in inflammatory pain conditions. The goal of this research was to test if BoNT/A was able to relieve also neuropathic pain symptoms. By using chronic constriction injury of the sciatic nerve, a mouse model of neuropathic pain, we observed that peripheral administration of BoNT/A strongly reduced the mechanical allodynia associated with this neuropathy. Remarkably, a single non-toxic dose of BoNT/A was sufficient to induce anti-allodynic effects, which lasted for at least 3 weeks. This result is particularly relevant since neuropathic pain is poorly treated by current drug therapies. This communication enlarges our knowledge on potentially new medical uses of BoNT/A in efforts to amelio- rate human health conditions, with very important implica- tions in the development of new pharmacotherapeutic ap- proaches against neuropathic pain. © 2006 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: sciatic nerve ligation, mechanical allodynia, be- havior, mice. Neuropathic pain, a major clinical and social problem, offers no biological advantages and causes suffering and distress (Loeser and Melzack, 1999). Such maladaptive pain is typi- fied by primary lesions or dysfunctions in the nervous system and derives from causes as diverse as disease states (can- cer, diabetes, multiple sclerosis, post-herpetic neuralgia, etc.) infectious or chemotherapeutic agents, physical trauma or surgery, and others (Woolf and Mannion, 1999). Neuropathic pain occurs with a complex combination of symptoms or sensory deficits, such as spontaneous pain, hyperalgesia and allodynia, whereby normally non-painful stimuli, such as light touch, become painful (Jensen et al., 2001; Zimmer- mann, 2001; Baron, 2006). Patients suffering neuropathic pain do not respond to conventional treatment with non- steroidal anti-inflammatory drugs (NSAIDs) and show a re- duced sensitivity to opiates often associated with side effects (Sindrup and Jensen, 1999). Usually they are treated empir- ically with antidepressants and anticonvulsants that have lim- ited efficacy and many undesirable side effects (Gilron and Max, 2005; Sindrup et al., 2005). In addition to current treat- ments, several new agents are under development (Dworkin et al., 2003; Ossipov and Porreca, 2005; Rice and Hill, 2006). The use of botulinum neurotoxins (BoNTs), as possible new analgesics, seems to be very attractive and should deserve particular attention from the scientific community. BoNTs are produced by the bacterium Clostridium botuli- num in seven different serotypes (Johnson, 1999). Al- though BoNTs are the most poisonous biological sub- stances known, they are widely employed in neurology for treatment of a variety of neuromuscular disorders (Davle- tov et al., 2005; Montecucco and Molgo, 2005). They act at the neuromuscular junction, where, by blocking neuro- transmission, they prevent the nerves from signaling mus- cles to contract (Simpson, 2004). Recently, very promising results on the analgesic role of BoNTs in inflammatory pain modulation have been published (Cui et al., 2004; Luvi- setto et al., 2006a). Their possible use in treatment of neuropathic conditions is still matter of intensive research and only few data in humans and animal models have been obtained (Bach-Rojecky et al., 2005; Liu et al., 2006; Park et al., 2006). In the present research, by using the chronic constric- tion injury (CCI) as an animal model of neuropathic pain (Bennett and Xie, 1988), we demonstrated the anti-allo- dynic efficacy of botulinum neurotoxin serotype A (BoNT/A) in relieving neuropathic pain symptoms. A single dose of BoNT/A, injected into the injured hind paw, was sufficient to reduce the mechanical allodynia and this re- duction was maintained for a long time without needing to repeat the treatment. The results of this research open a promising scenario on the development of new pharmaco- therapeutic approaches against neuropathic pain. EXPERIMENTAL PROCEDURES All procedures were in strict accordance with the Italian national law (DL116/92, application of the European Communities Council Directive 86/609/EEC) on the care and handling of animals and with the guidelines of the Committee for Research and Ethical Issues of IASP (PAIN ® 1983, 16, 109 –110). To minimize animal suffering, the minimum number of mice necessary for each ex- periment was used. *Corresponding author. Tel: +39-06-501703271; fax: +39-06-501703304. E-mail address: flaminia.pavone@ipsifar.rm.cnr.it (F. Pavone). Abbreviations: BoNT/A, botulinum neurotoxin serotype A; BoNT, bot- ulinum neurotoxin; CCI, chronic constriction injury. Neuroscience 145 (2007) 1– 4 0306-4522/07$30.00+0.00 © 2006 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2006.12.004 1