Harnessing the knowledge of animal toxins to generate drugs.

Animal toxins present high selectivity and specificity for their molecular targets, and have long been considered as prototypes for developing novel drugs, with some successful cases. In this regard, the variety of molecules found in animal venoms, which can be capable of affecting vital physiological systems, have providing the development of studies focusing on turning those molecules (toxins) into therapeutics to treat several diseases, such as chronic pain, hypertension, thrombosis, cancer, and so on. However, some important issues have been responsible for disrupting the toxin-based drug discovery projects. In this review, we have briefly highlighted the development of drugs based on animal toxins, discussing some successful cases as well as the main causes of failure, pointing out the recent strategies applied to overcome the difficulties related to the translational process in this kind of development scenario.

Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine.

BACKGROUND AND PURPOSE: Crotalphine is an antinociceptive peptide that, despite its opioid-like activity, does not induce some of the characteristic side effects of opioids, and its amino acid sequence has no homology to any known opioid peptide. Here, we evaluated the involvement of the peripheral cannabinoid system in the crotalphine effect and its interaction with the opioid system. EXPERIMENTAL APPROACH: Hyperalgesia was evaluated using the rat paw pressure test. Involvement of the cannabinoid system was determined using a selective cannabinoid receptor antagonist. Cannabinoid and opioid receptor activation were evaluated in paw slices by immunofluorescence assays using conformation state-sensitive antibodies. The release of endogenous opioid peptides from skin tissue was measured using a commercial enzyme immunoassay (EIA). KEY RESULTS: Both p.o. (0.008-1.0 µg·kg(-1) ) and intraplantar (0.0006 µg per paw) administration of crotalphine induced antinociception in PGE2 -induced hyperalgesia. Antinociception by p.o. crotalphine (1 µg·kg(-1) ) was blocked by AM630 (50 µg per paw), a CB2 receptor antagonist, and by antiserum anti-dynorphin A (1 µg per paw). Immunoassay studies confirmed that crotalphine increased the activation of both κ-opioid (51.7%) and CB2 (28.5%) receptors in paw tissue. The local release of dynorphin A from paw skin was confirmed by in vitro EIA and blocked by AM630. CONCLUSIONS AND IMPLICATIONS: Crotalphine-induced antinociception involves peripheral CB2 cannabinoid receptors and local release of dynorphin A, which is dependent on CB2 receptor activation. These results enhance our understanding of the mechanisms involved in the peripheral effect of crotalphine, as well as the interaction between the opioid and cannabinoid systems.