The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain

Abstract

This study assessed the effects of two N-acylethanolamides in established rat models of visceral and somatic inflammatory pain. (1) The therapeutic effects of the cannabinoid anandamide and the putative CB2 agonist palmitoylethanolamide were tested in a model of persistent visceral pain (turpentine inflammation of the urinary bladder). Both anandamide (at a dose of 25 mg/kg) and palmitoylethanolamide (at doses of 10-30 mg/kg) were able to attenuate the viscero-visceral hyper-reflexia (VVH) induced by inflammation of the urinary bladder. (2) The effects of the same compounds on the behavioural response to subcutaneous formalin injection were assessed. The characteristic biphasic response was observed in control animals. Anandamide (dose range 5-25 mg/kg) and palmitoylethanolamide (dose range 5-10 mg/kg) both reduced the second phase of the response. The results confirm the analgesic potential of endogenous ligands at cannabinoid receptor sites. The anti-nociceptive effect of the putative CB2 receptor agonist, palmitoylethanolamide, is particularly interesting since it is believed to be a peripherally mediated effect. This observation might be exploited to separate central psychotropic effects from peripheral analgesic actions of the cannabinoids, under inflammatory conditions.

Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide

“…Further support to this proposal comes from the fact that palmitylethanolamide may exert both analgesic Ž . Calignano et al, 1998;Jaggar et al, 1998; present study Ž and anti-inflammatory effects Benvenuti et al, 1968;Facci . et al, 1995;Mazzari et al, 1996 .…”

“…rodents Calignano et al, 1998;Jaggar et al, 1998 . In the present study, we have further characterized the antinociceptive activity of this endogenous lipid molecule in several models of phasic and tonic pain.…”

“…review . In addition to these centrally mediated effects, cannabinoids may also act at peripheral sites to reduce pain and hyperalgesia evoked by irritant chemicals such as Ž formalin, turpentine and carrageenan Calignano et al, 1998;Jaggar et al, 1998;Ko and Woods, 1999;Richard-. son et al, 1998 .…”

“…three decades ago Bachur et al, 1965 , was shown to have Ž marked anti-inflammatory Benvenuti et al, 1968;Facci et . al., 1995;Mazzari et al, 1996 and antinociceptive effects Ž when administered as a drug Calignano et al, 1998;. Jaggar et al, 1998 Calignano et al, 1998Calignano et al, , 2000 .…”

Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide

“…However, more recent data have indicated that PEA does not bind with high a nity to either of the two cannabinoid receptor subtypes (Showalter et al, 1996;antagonizing in¯ammatory processes (Facci et al, 1995;Mazzari et al, 1996). Furthermore, peripheral administration of PEA produces an analgesic e ect in formalin-induced in¯ammatory pain (Jaggar et al, 1998;Calignano et al, 1998), and the PEA-induced anti-nociceptive e ects are believed to be mediated by a peripheral CB 2 -like receptor. This is of particular pharmacological interest since PEA, in contrast to AEA, has no action on central CB 1 receptors, and so is unlikely to produce unwanted psychotropic e ects.…”