Abstract
BackgroundManagement of pain involves a balance between inhibition of pain and minimization of side effects; therefore, in developing new analgesic compounds, one must consider the effects of treatment on both pain processing and behavior. The purpose of this study was to evaluate the effects of the mu and kappa-2 opioid receptor agonists on general and pain behavioral outcomes.MethodsAs a general behavioral assessment, we modified the cylinder rearing assay and recorded the number and duration of rearing events. Thermal sensitivity was evaluated using either a reflexive measure of hindpaw withdrawal latency to a radiant heat source or using an orofacial operant thermal assay. Acetic acid-induced visceral pain and capsaicin-induced neurogenic inflammatory pain were used as painful stimuli. The mu-opioid receptor agonist, morphine or the kappa-2 receptor agonist GR89696 was administered 30 min prior to testing. A general linear model repeated measures analysis was completed for baseline session comparisons and an analysis of variance was used to evaluate the effects of treatment on each outcome measure (SPSS Inc). When significant differences were found, post-hoc comparisons were made using the Tukey honestly significant difference test. *P < 0.05 was considered significant in all instances.ResultsWe found that morphine and GR89,696 dose-dependently decreased the number of reaching events and rearing duration. Rearing behavior was not affected at 0.5 mg/kg for morphine, 1.25 × 10-4 mg/kg for GR89,696. Hindpaw thermal sensitivity was significantly increased only at the highest doses for each drug. At the highest dose that did not significantly influence rearing behavior, we found that visceral and neurogenic inflammatory pain was not affected following GR89,696 administration and morphine was only partially effective for blocking visceral pain.ConclusionThis study demonstrated that high levels of the opioids produced significant untoward effects and made distinguishing an analgesic versus a more general effect more difficult. Quantification of rearing behavior in conjunction with standard analgesic assays can help in gaining a better appreciation of true analgesic efficacy of experimental drugs.
Highlights
Management of pain involves a balance between inhibition of pain and minimization of side effects; in developing new analgesic compounds, one must consider the effects of treatment on both pain processing and behavior
In addition to performing binding studies demonstrating the presence of kappa-2 receptors, Caudle and Finegold et al found that U69,593, a kappa-1 receptor selective agent, has no analgesic effect when injected intrathecally in rats [13] whereas [methyl-4-[3,4-dichlorophenyl)acetyl]-3[1-pyrrolidinyl)methyl]-1-piperazinecarboxylate] (GR89,696), a putative kappa-2 opioid receptor agonist, has very potent antihyperalgesic actions [14,15]
W Figeufroeun4d that GR89,696 does not affect operant thermal outcome measures We found that GR89,696 does not affect operant thermal outcome measures
Summary
Management of pain involves a balance between inhibition of pain and minimization of side effects; in developing new analgesic compounds, one must consider the effects of treatment on both pain processing and behavior. In addition to performing binding studies demonstrating the presence of kappa-2 receptors, Caudle and Finegold et al found that U69,593, a kappa-1 receptor selective agent, has no analgesic effect when injected intrathecally in rats [13] whereas [methyl-4-[3,4-dichlorophenyl)acetyl]-3[1-pyrrolidinyl)methyl]-1-piperazinecarboxylate] (GR89,696), a putative kappa-2 opioid receptor agonist, has very potent antihyperalgesic actions [14,15]. In guinea pig hippocampal slices it has been demonstrated that kappa-1 receptors primarily inhibited glutamate release while kappa receptor activation suppressed NMDA receptor function [16,17,18]. These data are supported by the work of Schoffelmeer et al [19], Ohsawa and Kamei [20], and Gu et al [21]. The anti-allodynic and -hyperalgesic effects of GR89,696 are proposed to be a result of spinal kappa-2 opioid receptor activation and subsequent inhibition of spinal NMDA receptors [1416]
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