EFFECT OF CHRONIC ADMINISTRATION OF DIHYDROPYRIDINE CA2-INDUCED TOLERANCE TO MU-OPIOID AND KAPPA-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS( CHANNEL LIGANDS ON SUFENTANIL)
Jv. Garaulet et al., EFFECT OF CHRONIC ADMINISTRATION OF DIHYDROPYRIDINE CA2-INDUCED TOLERANCE TO MU-OPIOID AND KAPPA-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS( CHANNEL LIGANDS ON SUFENTANIL), Regulatory peptides, 63(1), 1996, pp. 1-8
The present investigation was aimed at elucidating if the entry of Ca2
+ plays a role in the development of tolerance to mu- and kappa-opioid
agonists in the guinea pig ileum myenteric plexus. For this purpose,
the influence of the L-type Ca2+ channel modulators nimodipine (Ca2+ b
locker) and Bay K 8644 (Ca2+ activator) on the expression of tolerance
to the inhibitory effects of mu- and kappa-opioid agonists in the ile
um of guinea pigs rendered tolerant to sufentanil was investigated. Ch
ronic perfusion of guinea pigs with nimodipine (2 mu g/mu l/h for 7 da
ys) or Bay K 8644 (0.5 mu g/mu l/h for 7 days) did not cause any modif
ication of the height of contractions induced by electrical stimulatio
n of the myenteric plexus-longitudinal muscle (MPLM) strip from naive
animals. Tolerance to sufentanil (a selective mu-agonist) was induced
by s.c. implantation of osmotic minipumps for 7 days, which deliver at
2 mu g/mu l/h. Control groups received saline. Tolerance to sufentani
l as well as to U-50,488H (selective kappa-agonist) was observed follo
wing chronic treatment with sufentanil and was revealed as a rightward
shift of the concentration-response curves. Chronic perfusion of guin
ea pigs with the Ca2+ antagonist nimodipine concurrently with chronic
sufentanil, markedly blocked the expression of tolerance to sufentanil
, as well as the cross-tolerance between sufentanil and U-50,488H. On
the contrary, when guinea pigs were perfused with the Ca2+ agonist Bay
K 8644 concurrently with sufentanil, it enhanced the magnitude of tol
erance to both sufentanil and U-50,488H. These results suggest that, i
n guinea pig ileum, chronic exposure to opioids may involve the activa
tion of L-type Ca2+ channel, which would indicate that intracellular C
a2+ may be one of the final pathways through which myenteric neurons a
dapt to the chronic opioid exposure.