dizocilpine-maleate and Drug-Hypersensitivity

Administration of opioid receptor agonists is followed by paradoxical sensory hypersensitivity. This hypersensitivity has been suggested to contribute to the antinociceptive tolerance observed with opioids. The authors hypothesized that alpha 2-adrenoreceptor agonists, which also produce antinociceptive tolerance, would produce sensory hypersensitivity.. alpha 2-Adrenoreceptor agonists were administered to male Sprague-Dawley rats as a single subcutaneous injection, a continuous subcutaneous infusion, a single intrathecal injection, or a continuous intrathecal infusion. Thermal sensitivity was determined using latency to withdrawal of the hind paw from radiant heat. Tactile sensitivity was determined using withdrawal threshold to von Frey filaments. Spinal dynorphin content was measured by enzyme immunoassay.. Single systemic or intrathecal injections of clonidine or dexmedetomidine produced antinociception followed by delayed thermal and tactile hypersensitivity. Six-day systemic or intrathecal infusion of clonidine produced tactile and thermal hypersensitivity observed even during clonidine infusion. Sensory hypersensitivity was prevented by coadministration of the alpha 2-adrenoreceptor-selective antagonist idazoxan or the N-methyl-D-aspartate receptor-selective antagonist MK-801. Six-day infusion of intrathecal clonidine increased dynorphin content in dorsal lumbar spinal cord. MK-801 and dynorphin antiserum reversed clonidine-induced sensory hypersensitivity.. alpha 2-Adrenoreceptor agonists produce sensory hypersensitivity that may be analogous to that produced by opioids. Sensory hypersensitivity was prevented by idazoxan, demonstrating that it is mediated by alpha 2 receptors. Clonidine infusion increased spinal dynorphin content. Sensory hypersensitivity was prevented or reversed by MK-801 and dynorphin antiserum, implicating N-methyl-D-aspartate receptors and spinal dynorphin in its production. Clinicians should be mindful of the possibility of drug-induced hyperalgesia in patients treated with alpha 2-adrenoreceptor agonists.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Clonidine; Dizocilpine Maleate; Drug Hypersensitivity; Male; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2

Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state-dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.

Topics: Amphetamine; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Hypersensitivity; Excitatory Amino Acid Antagonists; Male; Motor Activity; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Chloride

MK801 (MK), an N-methyl-D-aspartate (NMDA) receptor antagonist, attenuates tolerance to spinal opioids. Whether this applies to other G-protein-coupled receptor systems is unknown. This study examines the effects of continuous spinal MK on tolerance to the antinociceptive effect of continuous spinal infusion of the alpha-2 agonist ST91 (ST). Intrathecal (i.t.) infusion pumps were implanted in rats which delivered for 7 days: saline (1 microl/h); ST (40 nmol/microl/h); MK (10 nmol/microl/h) + ST (40 nmol/microl/h); or MK (10 nmol/microl/h). Antinociception was measured daily on the hot plate. On day 8, groups received i.t. boluses of ST to generate dose-response curves. A separate ST-infused group received MK (10 nmol i.t.) on day 7. Each group received ST (40 nmol i.t.) 7 days after discontinuation of infusion. Co-infusion of MK with ST resulted in attenuation of the right shift in dose response seen in ST-infused rats and a small preservation of effect on daily testing. However, MK-infused rats showed a significant left shift in ST dose response. Acutely administered, MK did not restore ST sensitivity. One week after cessation of infusion, ST and ST + MK groups showed shorter duration of effect after i.t. ST bolus than controls. In conclusion, chronic spinal MK partially attenuates loss of sensitivity to chronic spinal ST. This supports the hypothesis that opioid- and adrenoceptor-induced tolerances are similarly modulated by the NMDA receptor. However, the increased sensitivity induced by MK alone suggests that NMDA receptor antagonism may not prevent the development of tolerance itself but may alter the expression of tolerance by inducing sensitivity via other alterations in cellular function.

Topics: Adrenergic alpha-Agonists; Animals; Clonidine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Hypersensitivity; Injections, Spinal; Male; Pain; Rats; Rats, Sprague-Dawley; Reaction Time