Dissociation of tolerance and dependence for opioid peripheral antinociception in rats

Abstract

Repeated peripheral administration of the micro-opioid agonist [D-Ala2,N-Me-Phe4,gly5-ol] enkephalin (DAMGO) produces acute tolerance and dependence on its peripheral antinociceptive effect against prostaglandin E2 (PGE2)-induced mechanical hyperalgesia. In this study we evaluated the roles of protein kinase C (PKC) and nitric oxide (NO) in the development of this tolerance and dependence. Repeated administration of PKC inhibitors chelerythrine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride with DAMGO did not alter the tolerance to DAMGO; however, dependence (defined as naloxone-induced withdrawal hyperalgesia) was blocked. Repeated administration of N-(n-heptyl)-5-chloro-1-naphthalenesulfonamide, a PKC activator, which alone did not produce tolerance, mimicked the dependence produced by DAMGO. Repeated administration of the NO synthase inhibitor NG-methyl-L-arginine with DAMGO blocked the development of tolerance to DAMGO but had no effect on the development of dependence. Repeated administration of L-arginine, a NO precursor, mimicked tolerance produced by repeated administration of DAMGO (i.e. , the antinociceptive effect of DAMGO was lost); however, L-arginine did not mimic dependence. These findings suggest that the development of acute tolerance and dependence on the peripheral antinociceptive effects of DAMGO have different, dissociable mechanisms. Specifically, PKC is involved in development of mu-opioid dependence, whereas the NO signaling system is involved in the development of mu-opioid tolerance.

Fig. 1.

Effect of PGE₂ (100 ng,PGE2; n = 24), DAMGO (1 μg) plus PGE₂ (DAMGO+PGE2; n = 24), chelerythrine (1 μg) hourly × 3 and at the fourth hour PGE₂ (Chx3,PGE2; n = 12) or DAMGO plus PGE₂ (Ch×3,DAMGO+PGE2;n = 12), H-7 hourly × 3 and at the fourth hour DAMGO plus PGE₂ (H7×3,DAMGO+PGE2;n = 12), DAMGO hourly × 3 and at the fourth hour DAMGO plus PGE₂ (DAMGO×3,DAMGO+PGE2;n = 18), chelerythrine plus DAMGO hourly × 3 and at the fourth hour DAMGO plus PGE₂[(Ch+DAMGO)×3,DAMGO+PGE2; n = 12], H-7 plus DAMGO hourly × 3 and at the fourth hour DAMGO plus PGE₂ [(H7+DAMGO)×3,DAMGO+PGE2;n = 12] on mechanical paw-withdrawal threshold. In this and subsequent figures, * p < 0.05;NS, not statistically significant.

Fig. 2.

Effect of DAMGO hourly × 3 and at the fourth hour naloxone (DAMGO×3,Nal;n = 16), vehicle (saline) hourly × 3 and at the fourth hour naloxone methyliodide (Veh×3,Nal;n = 6), chelerythrine plus DAMGO hourly × 3 and at the fourth hour naloxone methyliodide [(Ch+DAMGO)×3,Nal; n = 12], H-7 plus DAMGO hourly × 3 and at the fourth hour naloxone methyliodide [(H7+DAMGO)×3,Nal; n= 12] on mechanical paw-withdrawal threshold.

Fig. 3.

A, Effect of SC-10 hourly × 3 (SC10×3; n = 16), SC-10 hourly × 3 and at the fourth hour PGE₂(SC10×3,PGE2; n = 6) or DAMGO plus PGE₂ (SC10×3,DAMGO+PGE2;n = 10), saline hourly × 3 and at the fourth hour DAMGO plus PGE₂ (Veh×3,DAMGO+PGE2;n = 8) on mechanical paw-withdrawal threshold.B, Effect of DAMGO hourly × 3 and at the fourth hour naloxone methyliodide (DAMGO×3,Nal;n = 16), DAMGO hourly × 3 and at the fourth hour vehicle (DAMGO×3,Veh; n = 6), SC-10 hourly × 3 and at the fourth hour naloxone methyliodide (SC10×3,Nal; n = 16), SC-10 hourly × 3 and at the fourth hour vehicle (SC10×3,Veh; n = 8), vehicle hourly × 3 and at the fourth hour naloxone methyliodide (Veh×3,Nal; n = 6) on mechanical paw-withdrawal threshold.

Fig. 4.

Effect of PGE₂ (PGE2), NMLA plus PGE₂ (NMLA+PGE2; n = 10), NMLA hourly × 3 (NMLA×3; n = 6), NMLA hourly × 3 and 72 hour post-PGE₂ [NMLA×3,PGE2(72 h post); n= 12], NMLA plus DAMGO hourly × 3 and PGE₂ 72 hour later [(NMLA+DAMGO)×3,PGE2(72 h post);n = 12], NMLA plus DAMGO hourly × 3 and 72 hr post DAMGO plus PGE₂[(NMLA+DAMGO)×3,DAMGO+PGE2(72 h post);n = 12], and DAMGO hourly × 3 and DAMGO plus PGE₂ 72 hr post [DAMGO×3,DAMGO+PGE2(72 h post); n = 8] on mechanical paw-withdrawal threshold.

Fig. 5.

Effect of DAMGO hourly × 3 and at the fourth hour naloxone methyliodide (DAMGO×3,Nal;n = 16), vehicle (saline) hourly × 3 and at the fourth hour naloxone methyl iodide (Veh×3,Nal;n = 6), NMLA plus DAMGO × 3 and at the fourth hour naloxone [(NMLA+DAMGO)×3, Nal;n = 10], NMLA plus DAMGO hourly × 3 and at the fourth hour saline [(NMLA+DAMGO)×3,Veh;n = 6] on mechanical paw-withdrawal threshold.

Fig. 6.

A, Effect of three hourly injections of vehicle (saline) (Veh×3; n = 6),l-arginine (100 ng) (L-Arg×1;n = 12), three hourly injections ofl-arginine (L-Arg×3; n= 12), 72 hr after three hourly injections of l-arginine [L-Arg×3(72hpost); n = 12], PGE₂ 72 hr after three hourly injections ofl-arginine [L-Arg×3,PGE2(72hpost);n = 6], PGE₂ (PGE2), DAMGO plus PGE₂ 72 hr after three hourly injections ofl-arginine [L-Arg×3,DAMGO+PGE2(72hpost);n = 12], DAMGO plus PGE₂(DAMGO+PGE2), on mechanical paw-withdrawal threshold.B, Effect of three hourly injections of DAMGO and 72 hr after naloxone methyliodide [DAMGO×3,Nal(72hpost)], naloxone methyl iodide 72 hr after three hourly injections ofl-arginine [L-Arg×3,Nal(72hpost);n = 8], vehicle 72 hr after three hourly injections of l-arginine [L-Arg×3,Veh(72hpost); n = 8], on mechanical paw-withdrawal threshold.