Actions of the Endocannabinoid Transport Inhibitor Am404 in Neuropathic and Inflammatory Pain Models

Abstract

1. Although cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central cannabinoid CB(1) receptor-mediated motor and psychotropic side-effects. The actions of endocannabinoids, such as anandamide, are terminated by uptake and subsequent intracellular enzymatic degradation. In the present study, we examined the effect of acute administration of the anandamide transport inhibitor AM404 in rat models of chronic neuropathic and inflammatory pain. 2. Systemic administration of AM404 (10 mg/kg) reduced mechanical allodynia in the partial sciatic nerve ligation (PNL) model of neuropathic pain, but not in the complete Freund's adjuvant (CFA) model of inflammatory pain. 3. The effect of AM404 in the PNL model was abolished by coapplication with the selective cannabinoid CB(1) receptor antagonist AM251 (1 mg/kg). AM404 did not produce a reduction in motor performance in either the PNL or CFA models. 4. These findings suggest that acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.

Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation

“…This anti-allodynic effect was blocked by the CB 2 receptor antagonist, SR144528, but not by rimonabant. In addition, AM404 blocked mechanical allodynia in rats subjected to partial nerve ligation (53). This effect was blocked by a CB 1 receptor antagonist; however, CB 2 receptor antagonists were not evaluated in this study.…”

Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

“…Högestätt et al (2005) have shown that the intermediate paracetamol metabolite, p-aminophenol, is converted in the brain into the novel metabolite AM404 through the action of FAAH (Högestätt et al, 2005). Before that, AM404 has been shown to induce analgesia (La Rana et al, 2006;Borsani et al, 2007;Mitchell et al, 2007) hypothermia at high doses in rats (Rawls et al, 2006). AM404 also acts as an activator of the TRPV1 channel (De Petrocellis et al, 2000) and inhibits COX-1 and COX-2 activities (Högestätt et al, 2005).…”

Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide

“…Our study might suggest that compounds capable to prolong the lifespan of anandamide by inhibiting its inactivation, and that have proved useful in several animal models of pain, inflammation, and itch (15,16,(41)(42)(43)(44)(45)(46)(47)(48), might not be necessarily suitable for the symptomatic treatment of candidiasis, as they might also promote the formation of 3-HAEA, a likely algogenic compound. Furthermore, our data provide an unusual example of the typical capability of pathogenic microorganisms to control, or even exploit, innate defense mechanisms to facilitate infection (49,50).…”

“…TRPV1 sensitization likely occurs during candidiasis, because increased expression of vulvar TRPV1 receptors is observed during vulvodynia, a condition similar to that caused by candidiasis (14), and clotrimazole, a widely used antimycotic agent, was suggested to owe its inflamma- tory and algogenic side effects to its capability to activate TRPV1 receptors (40). On the other hand, several peripheral inflammatory conditions causing pain and/or itch are known to be accompanied by elevated levels of anandamide as an adaptive reaction to counteract these symptoms, as suggested by the observation that compounds that prolong the life span of anandamide by inhibiting its inactivation exert anti-inflammatory effects (15,16,(41)(42)(43)(44)(45)(46)(47). Thus, it seems reasonable to hypothesize that, during candidiasisinduced inflammation, on the one hand TRPV1 is sensitized, and, on the other hand, anandamide is produced by host or neighboring cells.…”

“…In fact, it has been shown that vulvodynia, a condition characterized by painful burning sensation, allodynia, and hyperalgesia in the region of the vulval vestibules, is accompanied by increased expression of TRPV1 receptors (14). On the other hand, inflammatory conditions causing pain are known to be counteracted by compounds that elevate the tissue levels of anandamide by inhibiting its cellular uptake or, alternatively, by interfering with its enzymatic hydrolysis (15,16). Remarkably, there is also growing awareness that anandamide can activate TRPV1 receptors, especially during various inflammatory and pronociceptive conditions, and when its activity at CB 1 receptors is blocked and the sensitivity of TRPV1 receptors is enhanced by its phosphorylation or overexpression (17,18).…”