Assay Of Thermal Nociception Research Articles

Interactions between δ and μ Opioid Agonists in Assays of Schedule-Controlled Responding, Thermal Nociception, Drug Self-Administration, and Drug versus Food Choice in Rhesus Monkeys: Studies with SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and Heroin

Interactions between delta and mu opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the delta agonist SNC80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED50 = 0.43 mg/kg) and heroin (ED50 = 0.088 mg/kg) produced a dose-dependent and complete suppression of response rates in the assay of schedule-controlled responding. Heroin also produced thermal antinociception (ED(5 degrees C) = 0.18 mg/kg) and maintained drug self-administration under both a fixed ratio schedule [dose-effect curve peak at 0.0032 mg/kg/injection (inj)] and under a food versus heroin concurrent-choice schedule (ED50 = 0.013 mg/kg/inj), whereas SNC80 did not produce thermal antinociception or maintain self-administration. Fixed ratio mixtures of SNC80 and heroin (1.6:1, 4.7:1, and 14:1 SNC80/heroin) produced additive effects in the assay of schedule-controlled responding and superadditive effects in the assay of thermal nociception. Also, SNC80 did not enhance the reinforcing effects of heroin, indicating that mixtures of SNC80 and heroin produced additive or infra-additive reinforcing effects. These results provide additional evidence to suggest that delta/mu interactions depend on the experimental endpoint and further suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists while either not affecting or decreasing the sedative and reinforcing effects of mu agonists.

Sex differences in thermal nociception and prostaglandin-induced thermal hypersensitivity in rhesus monkeys

The present study examined thermal nociception in 4 male and 4 female rhesus monkeys. In the first experiment, monkeys were tested 5 days/week for 4 consecutive weeks in a warm-water, tail-withdrawal assay of thermal nociception. Thermal nociception did not vary by sex or menstrual cycle phase. However, male monkeys tended to be slightly more sensitive to thermal stimuli than female monkeys in the follicular phase of the menstrual cycle. Thermal nociception did not correlate with estradiol or progesterone levels in female monkeys. In the second experiment, thermal hypersensitivity was induced by administering prostaglandin E 2 (0.0032 to 0.1 mg subcutaneously) into the tail. Prostaglandin E 2 produced slightly greater thermal hypersensitivity in male than in follicular phase female monkeys, but male and luteal phase female monkeys did not differ, and there was not a significant difference between follicular and luteal phase female monkeys. Exposure to the behavioral procedures produced similar increases in blood levels of the stress-related hormones adrenocorticotropic hormone and cortisol in male and female monkeys, which suggests that measures of thermal nociception or thermal hypersensitivity were not confounded by sex differences in stress responses. These results suggest that sex and gonadal hormone levels have only a minor influence on thermal nociception or thermal hypersensitivity in rhesus monkeys. Perspective These modest effects of sex and gonadal hormone levels on measures of pain in non-human primates could be interpreted to support the hypothesis that sex differences in pain perception in humans are due more to sociocultural factors than to a biological imperative.

Opioid interactions in rhesus monkeys: effects of delta + mu and delta + kappa agonists on schedule-controlled responding and thermal nociception.

Agonists at delta, mu, and kappa opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha,7alpha,8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint.

Effects of heroin and its metabolites on schedule-controlled responding and thermal nociception in rhesus monkeys: sensitivity to antagonism by quadazocine, naltrindole and ß-funaltrexamine

Recent studies have reported differences in the receptor mechanisms and intrinsic efficacies of heroin and its metabolites 6-acetylmorphine and morphine in rodents. The present study examined the generality of these findings to rhesus monkeys using two behavioral procedures. In an assay of schedule-controlled behavior, response rates were recorded under a fixed-ratio 30 schedule of food presentation. In an assay of thermal nociception, tail-withdrawal latencies were measured from warm water (42–58 °C). Heroin, 6-acetylmorphine and morphine produced dose-dependent rate-decreasing and antinociceptive effects. Antagonism studies were conducted with the competitive mu-selective antagonist quadazocine, the competitive delta-selective antagonist naltrindole, and the irreversible mu-selective antagonist ß-funaltrexamine (ß-FNA). Quadazocine dose-dependently antagonized the effects of all three opioids. Quadazocine pA2 values were similar across drugs and assays (7.4–7.8) and similar to quadazocine pA2 values for antagonism of other mu agonists. In contrast, naltrindole did not alter the effects of any of the opioids. ß-FNA antagonized the rate-decreasing and antinociceptive effects of heroin and morphine. Dose-effect data for heroin- and morphine-induced antinociception alone and after ß-FNA treatment were used to estimate in vivo apparent efficacy values (tau). Tau values (95% confidence limits) were 8.1 (6.9–9.6) for heroin and 2.6 (2.5–2.9) for morphine, but this difference is relatively small. These results suggest that the rate-decreasing and antinociceptive effects of heroin, 6-acetylmorphine and morphine are mediated by pharmacologically similar populations of mu opioid receptors in rhesus monkeys. The in vivo apparent efficacy of heroin at mu receptors was similar to or only slightly greater than that of morphine.

Sex differences in opioid antinociception in rhesus monkeys: Antagonism of fentanyl and U50,488 by quadazocine

Sex differences have been observed in the antinociceptive effects of opioids in rodents and rhesus monkeys. Sex differences in the affinity of opioid ligands for opioid receptors may contribute to these findings. To test this hypothesis, the relative affinity of the competitive opioid antagonist quadazocine for μ and κ opioid receptors was determined in rhesus monkeys using in vivo pA2 analysis. The antinociceptive effects of the μ opioid agonist fentanyl and the κ opioid agonist U50,488 were determined alone and after pretreatment with quadazocine in 4 females and 4 males using a warm-water tail-withdrawal assay of thermal nociception. The relative potency of quadazocine antagonism of fentanyl and U50,488 in females and males was used to assess sex differences in the relative affinity of quadazocine for μ and κ receptors. Fentanyl was equipotent in female and male monkeys, and quadazocine was equipotent as an antagonist of fentanyl in females and males. In contrast, U50,488 was significantly less potent in females, and quadazocine was less potent as an antagonist of U50,488 in females. These findings suggest that opioid ligands have similar affinity for μ receptors but lower affinity for at least some κ receptors in female than in male rhesus monkeys. © 2002 by the American Pain Society

Contribution of the site of heating to variability in the latency of the rat tail flick reflex

The rat tail flick reflex is a commonly used assay of thermal nociception. Variability in the latency to respond due to the locus of tail heating was examined in spinalized (midthoracic) rats and evaluated retrospectively using data from two previously published studies. In all 3 sets of data, a significant relation was found between the proximal-distal site of heating on the tail and the latency of the tail flick reflex. Heating of the most distal sites resulted in shortest response latencies.