The effect of botulinum toxin type a on neural activation in the region of the trigeminal caudal nucleus in a model of inflammatory pain induced by formalin

Abstract

Bol kroničnog trajanja je veliki problem u svijetu i u mnogim se slučajevima ona ne može uspješno kontrolirati konvencionalnim analgeticima. Tijekom posljednja tri desetljeća u nekliničkim i kliničkim istraživanjima pokazan je potencijal botulinum toksina tipa A (BT-A) u nanogramskim dozama u smanjenju i dugotrajnoj kontroli kronične boli različite etiologije. Međutim, njegov mehanizam djelovanja na patološku bolnu preosjetljivost nije do kraja poznat. Dosadašnja istraživanja pokazala su da BT-A s perifernog mjesta primjene retroaksonalnim transportom putuje u središnji živčani sustav gdje modulira djelovanje različitih neurotransmiterskih sustava, da bi najnovija istraživanja sugerirala i njegov među-sinaptički prijenos. U ovom diplomskom radu je istraženo središnje antinociceptivno djelovanje periferno jednostrano primjenjenog BT-A u modelu upalne boli izazvane bilatralnom primjenom formalina u području njuške štakora. Praćenjem ekspresije c-Fos-a pokazano da BT-A smanjuje neuralnu aktivaciju u neuronima TNC-a na strani na kojoj je primjenjen, ali i na suprotnoj strani, pri čemu neutralizirajući antitoksin za BT-A poništava to djelovanje na obje strane. Rezultati ovog rada se slažu s do sada provedenim istraživanjima i upućuju na među-sinaptički prijenos kao važan čimbenik u kompleksnom mehanizmu antinociceptivnog djelovanja BT-A.Chronic pain is big health-care issue worldwide, and in many cases, it cannot be completely resolved with conventional analgetics. Over the past three decades, non-clinical and clinical research demonstrated that in nanogram concentrations, botulinum toxin type A (BT-A) has potential to alleviate and long-term control chronic pain of various etiologies. However, its mechanism of action on pathological pain hypersensitivity is not fully understood. So far, researchers have shown that BT-A travels from peripheral application site to central nervous system via retrograde axonal transport, where it modulates different neurotransmitter systems, and the latest research suggests transynaptic transmission. In this master’s thesis, the central antinocieptive action of unilaterally, peripherally applied BT-A, was investigated in the inflammatory pain model caused by bilateral application of formalin to the rat whisker pad. By monitoring expression of c-Fos as a marker of neural activation, it was shown that BT-A reduces neural activation in the neurons of the TNC region on the side of the application as well as on the opposite side, whilst neutralizing BT-A antitoxin reverses BT-A effect on both sides. Obtained results in this master’s thesis are consistent with previous studies and indicate that transynaptic transmission is one of the important factors in the complex antinociceptive mechanism of BT-A