The selective mu-
opioid agonist, D-Ala2,N-Me-Phe4,Gly5-ol-enkephalin (
DAMGO), or the selective A1-adenosine agonist
N6-cyclopentyladenosine (CPA), when coinjected intradermally with
prostaglandin E2 (
PGE2), dose-dependently inhibited PGE2-induced
mechanical hyperalgesia in the rat hindpaw, as determined by the Randall-Selitto paw-withdrawal test. Repeated (hourly x 3)
intradermal injections of
DAMGO or CPA produced tolerance to the antinociceptive effect of a fourth injection 1 hr later. Furthermore, repeated (hourly x 3)
intradermal injections of
DAMGO produced cross-tolerance to the antinociceptive effect of CPA, and repeated (hourly x 3)
intradermal injection of CPA produced cross-tolerance to the antinociceptive effect of
DAMGO. The demonstration of the bidirectional cross-tolerance between the peripheral antinociceptive effects of
DAMGO and CPA supports the hypothesis that both these agents produced antinociception by acting on the same cell, presumably the primary afferent nociceptor, and that the development of tolerance involves changes downstream to activation of mu-
opioid and A1-adenosine receptors. The
opioid antagonist naloxone, which had no effect on paw-withdrawal threshold in normal paws, produced withdrawal threshold in normal paws, produced withdrawal
hyperalgesia in
DAMGO-tolerant paws. Furthermore,
naloxone elicited a cross-withdrawal
hyperalgesia response in CPA-tolerant paws. Similarly, the A1-adenosine antagonist 1,3-dipropyl-8-(2-amino-4- chlorophenyl)-xanthine (
PACPX), which had no effect on paw-withdrawal threshold in normal paws, elicited a withdrawal
hyperalgesia response in CPA-tolerant paws and cross-withdrawal
hyperalgesia responses in
DAMGO-tolerant paws. These cross-dependence and cross-withdrawal responses suggest that the development of dependence to mu-
opioid and A1-adenosine agonists involves changes in the same second messenger system downstream to both mu-
opioid and A1-adenosine receptor activation.