Table 2. Peripheral lipid-mediated signaling as a source of new analgesic medicines.

The current therapy of chronic pain relies heavily on opiates (e.g., morphine and oxycodone) and anticonvulsants (e.g., gabapentin and pregabalin), two classes of drugs that primarily act on neural circuits of the brain and spinal cord. These agents help many, but their use is associated with central side effects and abuse potential. The existence of peripheral lipid-mediated mechanisms that regulate the flow of nociceptive signals to the central nervous system (CNS) offers the opportunity to develop medications that control pain without producing undesired central effects. Activation of CB₁ cannabinoid receptors in the brain is psychotropic, but peripherally restricted CB₁ agonists or globally active CB₂ agonists (e.g., AM1241) reduce nociceptive responses in rodent models without eliciting overt signs of cannabinoid intoxication. Marked anti-nociceptive actions, mediated by CB₁ and/or CB₂ receptors, are also observed with inhibitors of the endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH, e.g. URB597 or URB937) and monoacylglycerol lipase (MGL, e.g. JZL184). PPAR-α-mediated antinociception can be achieved either using direct PPAR-α agonists, such as the endogenous ligand palmitoylethanolamide (PEA), or inhibitors of the PEA-hydrolyzing enzyme N-acylethanolamine acid amidase (NAAA, e.g. ARN077). Similar approaches may be used to exploit the analgesic properties of endogenous bioactive lipids generated by oxygenation of polyunsaturated fatty acids (PUFAs): inhibition of soluble epoxide hydrolase (sEH), which converts epoxygenated PUFAs into inactive dihydroxy-acids, and administration of resolvins both produce marked antinociception in rodent models.

Molecular Target	Representative Probe	Chemical Structure	Select Ref.
Peripheral CB1 receptor	Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone		32
CB2 receptor	AM1241		41
FAAH	URB597		98
Peripheral FAAH	URB937		57
MGL	JZL184		99
PPAR-α	Palmitoylethanolamide		76
NAAA	ARN077		100
Soluble EH	t-AUCB		89
CB1 receptor (Allosteric Modulation)	Lipoxin A4		92
ChemR32	Resolvin E1		88