Peripherally administered endogenous opioid agonist and NMDA receptor antagonist ligands might be beneficial in inflammatory pain. Because both drugs barely cross the blood-brain barrier, their local administration causes no central side effects.

1. Although it is well known that the combined administration of synthetic or plant-originated opioids with cannabinoids (CB) results in synergistic antinociception, the effects of combined administration of endogenous ligands acting at micro-opioid and CB receptors are not known. The aim of the present study was to determine the interaction between anandamide (AEA; a CB(1) receptor agonist) and endomorphin-1 (EM-1; a micro-opioid receptor agonist) after intrathecal administration. 2. Nociception was assessed by the paw-withdrawal test after carrageenan-induced inflammation in male Wistar rats. 3. Endomorphin-1 (16.4 pmol to 16.4 nmol) and AEA (4.3-288 nmol) alone dose-dependently decreased carrageenan-induced thermal hyperalgesia, although the highest dose of AEA also exhibited pain-inducing potential. The potency of AEA was approximately 59-fold lower than that of EM-1 (35% effective dose (ED(35)) 194.4 vs 3.3 nmol, respectively). Coadministration of these ligands revealed that combinations of 16.4 pmol EM-1 plus 28.8 or 86.5 nmol AEA were more effective than either drug alone, but other combinations were no more effective than the administration of EM-1 itself. Therefore, coadministration of AEA did not significantly shift the dose-response curve to EM-1. 4. The results of the present study indicate that the coadministration of AEA and EM-1 results in potentiated antihyperalgesia only for a combination of specific doses. Because AEA activates other receptor types (e.g. TRPV1) in addition to CB(1) receptors, the results of the present suggest that, after the coadministration of EM-1 and AEA, complex interactions ensue that may lead to different outcomes compared with those seen following the injection of exogenous ligands.

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.

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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.