glyceryl-2-arachidonate and Edema

Hemopressin, a nonapeptide (PVNFKFLSH: HP) derived from the α chain of hemoglobin was shown to interact specifically with brain cannabinoid CB(1) receptors. Therefore, it seems to be the only peptide structure with cannabinoid activities. Our goal in this study was to further characterize this peptide and to clarify the antinociceptive potency of the polyunsaturated fatty acid derivates, 2-arachidonoyl-glycerol (2-AG) and anandamide, by investigating their effects on mechanical allodynia at the spinal level.. HP was prepared on solid phase by in situ neutralization. After chronic intrathecal catheterization, mechanical hypersensitivity was produced in male Wistar rats by injection of carrageenan (300 μg/30 μL) into the tibiotarsal joint of one of the hind legs. Three hours after carrageenan administration, the ligands were administered intrathecally. The mechanical threshold was assessed using a dynamic aesthesiometer.. 2-AG (1-200 μg) and anandamide (10-200 μg) decreased carrageenan-induced mechanical allodynia in a dose-dependent manner, whereas HP had no antinociceptive effect in a wide dose range (0.3-30 μg). The effect of 2-AG was prevented by the CB(1) receptor antagonist AM 251, but not by the CB(2) antagonist SSR144528-2. HP (3 and 30 μg) also inhibited the effect of 2-AG. None of the ligands influenced the degree of edema.. HP posttreatment had no effect on mechanical allodynia, whereas spinally injected 2-AG and anandamide were potent drugs.

Topics: Analgesics; Animals; Arachidonic Acids; Arthralgia; Arthritis, Experimental; Cannabinoid Receptor Modulators; Carrageenan; Dose-Response Relationship, Drug; Edema; Endocannabinoids; Glycerides; Hemoglobins; Hindlimb; Injections, Spinal; Joints; Male; Pain Measurement; Pain Threshold; Peptide Fragments; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Time Factors

1. Both cannabinoid and opioid receptors are localized at the peripheral level, and drugs acting on these receptors may produce antinociception after topical administration; however, the effect of endogenous ligands at these receptors is poorly understood. Our goal was to determine the antinociceptive potency of the endogenous cannabinoid 2-arachidonoyl-glycerol (2-AG), and its interaction with endomorphin-1 (EM1) at joint level in the rat inflammation model. 2. Mechanical hypersensitivity was produced by injection of carrageenan (300 microg/30 microL) into the tibiotarsal joint of the right hind leg. The mechanical threshold was assessed by von Frey filaments. 2-AG (3-200 microg), EM1 (100-300 microg) and their combinations in a fixed-dose ratio (1 : 10) were given into the inflamed joint, and the threshold was determined repeatedly for 105 min after the drug administrations. 3. Both ligands produced dose-dependent anti-hyperalgesia, and the highest doses caused prolonged effects, but they did not influence the degree of oedema and the withdrawal threshold at the non-inflamed side. EM1 had lower potency compared to 2-AG (ED(25): 233 (CI: 198-268) microg and 126 (CI: 88-162) microg, respectively; P < 0.05). The effects of EM1 and 2-AG were prevented by mu-opioid and cannabinoid 1 receptor antagonists, respectively. The ED(25) value for the combination (98 (CI: 80-112) microg) did not differ significantly from the value of 2-AG; however, the largest dose combination produced a significantly higher effect than the ligands by themselves. 4. Our data showed that 2-AG was an effective antinociceptive ligand at joint level, and its combination with EM1 produced long-lasting, effective antinociception.

Topics: Analgesics, Opioid; Animals; Arachidonic Acids; Arthritis, Experimental; Cannabinoid Receptor Modulators; Dose-Response Relationship, Drug; Drug Synergism; Edema; Endocannabinoids; Glycerides; Ligands; Male; Narcotic Antagonists; Oligopeptides; Pain Threshold; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Opioid; Tarsal Joints