Pharmacological Research 66 (2012) 243–250 Contents lists available at SciVerse ScienceDirect Pharmacological Research jo ur n al hom epage: www.elsevier.com/locate/yphrs Palvanil, a non-pungent capsaicin analogue, inhibits inflammatory and neuropathic pain with little effects on bronchopulmonary function and body temperature Livio Luongo a,e , Barbara Costa b , Bruno D’Agostino b , Francesca Guida a , Francesca Comelli b , Luisa Gatta a , Maria Matteis b , Nikol Sullo b , Luciano De Petrocellis c,e , Vito de Novellis a,e , Sabatino Maione a,e , Vincenzo Di Marzo d,e,∗ a Department of Experimental Medicine – Division of Pharmacology “L. Donatelli”; Second University of Naples, Naples, Italy b Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy c Institute of Cybernetics, C.N.R., Pozzuoli (Naples), Italy d Institute of Biomolecular Chemistry, C.N.R., Via Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy e Endocannabinoid Research Group, Italy a r t i c l e i n f o Article history: Received 25 February 2012 Received in revised form 15 May 2012 Accepted 16 May 2012 Keywords: TRPV1 Vanilloid Pain Bronchoconstriction Neuropathic pain Inflammatory pain Capsaicin a b s t r a c t N-Palmitoyl-vanillamide (palvanil) is a non-pungent capsaicinoid, found in low amounts in Capsicum and shown to rapidly desensitize transient receptor potential vanilloid type-1 (TRPV1) channels to the action of capsaicin and to exert analgesic effects after local administration. We have investigated here if systemic administration of palvanil to mice causes two typical adverse events of TRPV1 agonists, i.e. profound changes in body temperature and bronchoconstriction, and if it can still produce effective inhi- bition of inflammatory and chronic pain in different experimental models. Varying doses of palvanil were tested subcutaneously and acutely on body temperature in vivo or, or as a bolus, on bronchopulmunary function ex vivo, in comparison with capsaicin. Intraperitoneal palvanil was also tested against formalin- induced nocifensive behavior and carrageenan-induced oedema and thermal hyperalgesia, acutely, and against mechanical allodynia and thermal hyperalgesia in mice with spared nerve injury (SNI) of the sci- atic nerve, after repeated administration over 7 days from SNI. Palvanil, at therapeutically relevant doses, produced significantly less hypothermia and bronchoconstriction than capsaicin. Palvanil (0.5–2.5 mg/kg) abolished formalin-induced nocifensive behavior and strongly attenuated SNI-induced mechanical allo- dynia and thermal hyperalgesia and carrageenan-induced oedema and thermal hyperalgesia. Systemic administration of the non-pungent capsaicinoid, palvanil, produces, at least in mice, much less of those side effects typical of TRPV1 agonists (hypothermia and bronchoconstriction), whilst being very effec- tive at reducing pain and oedema. Thus, palvanil might be developed further as a novel pharmacological treatment for chronic abnormal pain. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction The transient receptor potential vanilloid type-1 (TRPV1) chan- nel is a non-specific cation channel that plays a key role in nociceptive processes such as inflammatory hyperalgesia and tac- tile allodynia [1,2]. It is abundantly expressed on sensory afferent fibers of the A- and C-type and its activation in dorsal root ganglion neurones causes calcium entry and cell depolarization. This effect is responsible for local or distal release of algogenic ∗ Corresponding author at: Institute of Biomolecular Chemistry, C.N.R., Via Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy. E-mail address: vdimarzo@icmib.na.cnr.it (V. Di Marzo). peptides, such as calcitonin gene-related peptide and substance P, and, subsequently, for the activation of ascending pain transmis- sion [3]. Recently, the presence of TRPV1 in glutamatergic neurons in the brain has been highlighted [2,4–7]. TRPV1 exists in phosphorylated/active and dephosphory- lated/inactive forms, only the former being able to mediate the gating of extracellular calcium into nociceptive sensory neurons and their subsequent depolarization [8]. However, intracellular cal- cium increase leads to TRPV1 desensitization, through the action of Ca 2+ -sensitive phosphatases such as calcineurin [9]. As a con- sequence, TRPV1 becomes unresponsive to further stimulation by noxious heat or endogenous algogenic mediators, thus leading to paradoxical anti-hyperalgesic actions, which represent the ratio- nale of the use of capsaicin-based creams against chronic pain 1043-6618/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phrs.2012.05.005