Palmitoylethanolamide in spinal cord

Palmitoylethanolamide as a GPR55 agonist 

The endogenous lipid palmitoylethanolamide (PEA) and the CB1 receptor antagonist N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) are agonist with high affinity for GPR55 receptor.

The authors summarized the analgetic properties of PEA:

The anti-inflammatory and antinociceptive effects of PEA have been shown in previous studies. Oral administration of PEA led to a dose-dependent reduction in carrageenan and formalin induced hindpaw edema in laboratory animals. Other studies concluded that PEA has a curative as well as a prophylactic effect in certain models of acute inflammation.

Moreover, available evidence suggests that PEA is effective against acute pain, especially persistent somatic inflammatory pain in laboratory animals. PEA induced a dose-dependent inhibition of mechanical and thermal hyperalgesia following the sub-plantar injection of carrageenan.

Furthermore, an antinociceptive effect was observed as the reduction of pain behaviour elicited by subcutaneous formalin injection and by intraperitoneal injections of acetic acid, kaolin and magnesium sulphate.

In addition, it has been demonstrated that the intraperitoneal administration of PEA immediately after an intra-plantar injection of nerve growth factor (NGF) reduced the resulting NGF-induced thermal hyperalgesia.

Furthermore, they highligt the role of interleukin 1-beta (IL-1β) as a pro-inflammatory cytokine that is involved in pain and inflammation. In painmodels, were one produces mechanical or thermal hyperalgesia one sees hand in hand with the painstaqtes, an upregulation of inflammatory cytokines such as IL-1β in the inflamed tissue and in the dorsal root ganglia.

Objective of study:

The objective of this study was to investigate the possible involvement of spinal cannabinoid CB1 receptor as well as other cannabinoid related receptors, such as GPR55, in antinociceptive effect produced by intrathecal administration of PEA in rat. Moreover, spinal IL-1β levels as an inflammatory cytokine were measured in all groups.

Results: PEA and AM251 both decrease pain and IL1-β

Both PEA as well as AM251 decreased pain, also in combination, as well as the IL1-β level in the spinal cord!

Intrathecal (i.t.) administration of PEA (1, and10 μg) could significantly decrease both pain-related scores in the rat-pain-formalin test and also decrease the expression of  IL1-β  in the spinal cord.

Pretreatment of rats with low doses of CB1 receptor antagonist/GPR55 receptor agonist AM251 (10, 100 ng; i.t.), did not attenuated the effect of PEA, yet even significantly increased the effect of PEA on IL1-β expression in rat spinal cord.

Interestingly, i.t. administration of low doses of AM251 per se also significantly decreased both pain related behavior and spinal IL1-β expression in formalin test. 

Discussion by authors

These data suggested that the antinociceptive effect of PEA in spinal cord level is less likely due to its action on putative cannabinoid CB1/CB2 receptors because no inhibition of PEA analgesia was observed after pretreatment of rats with AM251.

The data also confirm the results of previous studies showing the CB1/CB2-independent antinociception and anti-inflammatory effects of PEA.

The fact that the anti-inflammatory properties of cannabinoids might be through receptors other than putative CB1 and CB2 has been shown in other study in which cannabidiol, a cannabinoid with no affinity to CB1/CB2 receptor, reduced IL1-β production in an experimental model of colitis  as well as in beta-amyloid induced neuroinflammatory responses.

Based on previous studies it is unlikely that antinociceptive effect of PEA is mediated through CB2 receptor.

The findings discussed here showed no hyperalgesic effect after AM251 i.t. administration per se which suggest the possible involvement of receptorial systems other than CB1 cannabinoid receptors in spinal antinociceptive pathway.

The authors finalized their paper concluding:

In conclusion, considering the antinociceptive effect of AM251 as a CB1 receptor antagonist/GPR55 receptor agonist and also the antinociceptive effect of PEA as a selective GPR55 agonist/weak cannabinoid receptor agonist, it could be suggested that GPR55 receptors are involved in pain modulation and could be considered as an important target for antinociceptive therapies.

Nonetheless, further experiments using a selective GPR55 receptor antagonist or GPR55−/− knockout animals would be required to confirm the GPR55-mediated antinociceptive action of AM251 and PEA.  [1]