Oleoylethanolamide (OEA) is a natural fatty acid amide that mainly modulates feeding and energy homeostasis by binding to peroxisome proliferator-activated receptor-alpha (PPAR-alpha) [Rodríguez de Fonseca F, Navarro M, Gómez R, Escuredo L, Navas F, Fu J, et al. An anorexic lipid mediator regulated by feeding. Nature 2001;414:209-12; Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodríguez de Fonseca F, et al. Oleoylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 2003;425:90-3]. Additionally, it has been proposed that OEA could act via other receptors, including the vanilloid receptor (TRPV1) [Wang X, Miyares RL, Ahern GP. Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J Physiol 2005;564:541-7.] or the GPR119 receptor [Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 2006;3:167-175], suggesting that OEA might subserve other physiological roles, including pain perception. We have evaluated the effect of OEA in two types of nociceptive responses evoked by visceral and inflammatory pain in rodents. Our results suggest that OEA has analgesic properties reducing the nociceptive responses produced by administration of acetic acid and formalin in two experimental animal models. Additional research was performed to investigate the mechanisms underlying this analgesic effect. To this end, we evaluated the actions of OEA in mice null for the PPAR-alpha receptor gene and compared its actions with those of PPAR-alpha receptor wild-type animal. We also compared the effect of MK-801 in order to evaluate the role of NMDA receptor in this analgesia. Our data showed that OEA reduced visceral and inflammatory responses through a PPAR-alpha-activation independent mechanism. Co-administration of subanalgesic doses of MK-801 and OEA produced an analgesic effect, suggesting the participation of glutamatergic transmission in the antinociceptive effect of OEA. This study represents a novel approach to the examination of the effectiveness of OEA in nociceptive responses and provides a framework for understanding its biological functions and endogenous targets in visceral and inflammatory pain.

Paclitaxel is an effective antineoplastic drug treatment used as an anti-tumoral therapy. Unfortunately its use is associated with unwanted side effects, which include the development of peripheral neuropathies and neuropathic pain, greatly affecting the quality of life of patients. It is well known that agonists of the cannabinoid receptor are able to reduce hyperalgesia and allodynia that develop after nerve injury. Our aim was to evaluate the efficacy of the cannabinoid agonist WIN 55,212-2 to reduce the thermal hyperalgesia and the tactile allodynia induced by administration of paclitaxel in rats. Present results demonstrate that WIN 55,212-2 (1 mg/kg i.p.) significantly reduced the heat (P<0.0001) and the mechanical (P=0.0003) withdrawal thresholds, the dose being smaller than that required to reach similar effects in the sciatic nerve constriction model (1.5 mg/kg). When the cannabinoid tetrad test was evaluated to measure behavioral modifications, it was found that WIN 55,212-2 (1mg/kg) did not induce changes either in body temperature or in immobility time, and only a reduction in spontaneous motility was recorded. This effect was antagonized by SR 141716A, suggesting the involvement of the CB1 receptor, although the participation of CB2 receptors cannot be excluded from this study. When WIN 55,212-2 was administered intraplantar, no differences were observed between the injected paw and the contralateral paw, suggesting that systemic mechanisms are needed to reach effectiveness. From these results we suggest that cannabinoids may be an interesting alternative to reduce neuropathic symptoms induced by paclitaxel, however more work is required to assess this possibility.

Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have demonstrated a role for this molecule and its LPA1 receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA1 receptor is involved in behavior. Here we studied the phenotype of maLPA1–null mice, which bear a targeted deletion at the lpa1 locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA1-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor coordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes, and coordinated limb use. At behavioral level, maLPA1-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA1 receptor may play a major role in both spatial memory and response to anxiety-like conditions.