n(6)-cyclohexyladenosine and Pain

Antinociception induced by the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is linked to opioid receptors. We studied the subtype of receptors to which CPA action is related, as well as a possible enhancement of antinociception when CPA is coadministered with opioid receptor agonists. Spinal cord neuronal nociceptive responses of male Wistar rats with inflammation were recorded using the single motor unit technique. CPA antinociception was challenged with naloxone or norbinaltorphimine. The antinociceptive activity of fentanyl and U-50488H was studied alone and combined with CPA. Reversal of CPA antinociception was observed with norbinaltorphimine (82.9±13% of control) but not with low doses of naloxone (27±8% of control), indicating an involvement of κ-opioid but not µ-opioid receptors. Low doses of CPA did not modify fentanyl antinociception. However, a significant enhancement of the duration of antinociception was seen when U-50488H was coadministered with CPA. We conclude that antinociception mediated by CPA in the spinal cord is associated with activation of κ-opioid but not µ-opioid receptors in inflammation. In addition, coadministration of CPA and κ-opioid receptor agonists is followed by significantly longer antinociception, opening new perspectives in the treatment of chronic inflammatory pain.

Topics: Adenosine; Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Fentanyl; Inflammation; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, kappa; Reflex; Spinal Cord

1. The present study examined the antinociceptive effects of carbamazepine on the tail flick test in stressed and nonstressed rats. 2. Carbamazepine produced a bimodal antinociceptive effect in stressed rats, the first peak appearing 30 min and the second 4 h after injection. Antinociceptive effect was not observed in nonstressed rats. 3. The secondary, but not the initial, carbamazepine antinociception in stressed rats was blocked by naloxone (0.2 mg/kg, i.p.), an opioid receptor antagonist. 4. Caffeine (5 mg/kg, i.p.), an adenosine A1/A2 receptor antagonist, inhibited the both initial and secondary antinociceptive effects of carbamazepine in stressed rats. 5. Carbamazepine increased the antinociceptive effect induced by either i.p. or i.c.v. administration of N6-cyclohexyl adenosine (CHA), an adenosine A1 receptor agonist, in stressed rats, but decreased it in nonstressed rats. 6. These results suggest that the initial antinociceptive effect of carbamazepine in stressed rats may be produced via an activation of the adenosine A1 receptors, such as was produced by CHA. The secondary long-lasting antinociceptive effects of carbamazepine may be mediated by an activation of opioid systems. 7. Furthermore, the initial activation of the adenosine A1 receptors by carbamazepine may be a triggering factor for the subsequent long-lasting activation of the opioid system, which results in the antinociception effects.

Topics: Adenosine; Analgesics, Non-Narcotic; Analysis of Variance; Animals; Caffeine; Carbamazepine; Cerebral Ventricles; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intraventricular; Male; Naloxone; Pain; Physical Stimulation; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Restraint, Physical; Stress, Psychological; Time Factors

Intrathecal (i.t.) coadministration of calcium (Ca2+), 50 micrograms potentiates the spinal antinociceptive action of morphine and noradrenaline (NA) but not cyclohexyladenosine, 5'-N-ethylcarboxamido adenosine or 5-hydroxytryptamine in the rat tail flick test. This dose of Ca2+ has no intrinsic effect in this test. Higher doses of Ca2+ (200-400 micrograms) produce antinociception in the tail flick and hot plate tests, which is completely blocked by pretreatment with the adenosine receptor antagonists theophylline, 50 micrograms and 8-phenyltheophylline, 3 micrograms. 8-Phenyltheophylline also eliminates potentiation of the antinociceptive action of NA by 50 micrograms Ca2+. The intrinsic antinociceptive effect of Ca2+ is blocked by i.t. pretreatment with the neurotoxins capsaicin, 50 micrograms and 6-hydroxydopamine, 50 micrograms but not 5,7-dihydroxytryptamine, 50 micrograms. Antinociception also is blocked by pretreatment with phentolamine but not by methysergide. These results suggest that the antinociceptive action of high doses of Ca2+ is due to release of adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. At lower doses, the release of adenosine is insufficient to cause antinociception, but potentiates the action of NA. Adenosine appears to originate from capsaicin-sensitive small diameter primary afferent nerve terminals. A subsequent interaction of adenosine with spinal adrenergic receptors contributes to antinociception.

Topics: 5,7-Dihydroxytryptamine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Calcium; Drug Synergism; Hot Temperature; Hydroxydopamines; Male; Methysergide; Norepinephrine; Oxidopamine; Pain; Phentolamine; Rats; Rats, Inbred Strains; Receptors, Purinergic; Serotonin; Spinal Cord; Theophylline

The effects on nociception, motor and autonomic function produced by the intrathecal administration of three adenosine analogs: N6-(L-2-phenylisopropyl)-adenosine, N6-cyclohexyladenosine and 5'-(N-ethylcarboxamido)-adenosine were examined in rats. Over the range of 0.3 to 1.0 nmol these agents produced a dose-dependent antinociception in the hot plate and tail-flick tests. In addition, 5'-(N-ethylcarboxamido)-adenosine and N6-(L-2-phenylisopropyl)-adenosine both suppressed the chemically evoked writhing response as well as the touch-evoked hyperesthesia normally observed in rats receiving low doses of intrathecal strychnine. These adenosine analogs examined at doses higher than 1.5 nmol produced a dose-dependent motor impairment as measured behaviorally and by electromyography, and an increase in the volume distention required to evoke micturition. Statistically significant effects on heart rate or blood pressure were not observed at any of the doses tested. The effects of the adenosine analogs on nociceptive and motor endpoints were partially antagonized by pretreatment with intrathecal caffeine (2 mumol). These results suggest a probable association of spinal adenosine receptors with a number of spinal sensory and motor systems other than those involved with nociceptive processing.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Autonomic Nervous System; Blood Pressure; Caffeine; Male; Movement; Pain; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Receptors, Purinergic; Spinal Cord; Urinary Bladder

Analogues of adenosine were injected intrathecally into rats implanted with chronic indwelling cannulae in order to determine a rank order of potency and hence characterize adenosine receptors involved in spinal antinociception. In the tail flick test L-N6-phenylisopropyl adenosine (L-PIA), cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) produced dose-related antinociception which attained a plateau level. NECA and CHA also produced an additional distinct second phase of antinociception. D-N6-Phenylisopropyl adenosine (D-PIA) and 2-chloroadenosine (CADO) had very little antinociceptive activity in this test. The rank order of potency in producing the plateau effect was L-PIA greater than CHA greater than NECA greater than D-PIA = CADO, while that for the second phase of antinociception was NECA greater than-CHA. Pretreatment with both theophylline and 8-phenyltheophylline (8-PT) antagonized antinociception produced by CHA, with 8-PT being at least an order of magnitude more potent than theophylline. Both antagonists produced a significant hyperalgesia in the tail flick test. L-PIA and CHA also produced methylxanthine-sensitive antinociception in the hot plate test. These results suggest that activation of A1-receptors in the spinal cord can produce antinociception. Activation of A2-receptors may produce an additional effect, but the relative activity of CHA in this component of activity is unusual.

Topics: 2-Chloroadenosine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Dose-Response Relationship, Drug; Male; Pain; Phenylisopropyladenosine; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Purinergic; Spinal Cord; Theophylline