Patricia F. Osgood

The Hemodynamic and Metabolic Interrelationships in the Activity of Epinephrine, Norepinephrine and the Thyroid Hormones

The hemodynamic and metabolic effects of a total sympathetic block and of the infusion of l-epinephrine or l-norepinephrine were studied in 27 euthyroid dogs and in 31 thyroid-fed dogs. The physiologic changes produced by increased concentrations of the thyroid hormones were abolished by preventing the reflex release of epinephrine and norepinephrine with a total sympathetic block. The inotropic, chronotropic and calorigenic effects of l-epinephrine and of l-norepinephrine were found to be increased by thyroid feeding. It is concluded that there is a dynamic interrelationship between the thyroid hormones and those of the adrenal medulla and sympathetic nerve endings. The hemodynamic and metabolic changes of thyrotoxicosis are not the result of the isolated activity of the thyroid hormones, but rather are due to the physiologic effects of epinephrine and norepinephrine, as augmented by the thyroid hormones. Studies indicate that l-norepinephrine is the predominant mediator of the changes produced by thyroid feeding.

The assessment of pain and plasma β-endorphin immunoactivity in burned children☆

&NA; The need for better analgesia during burn dressing changes (BDCs) in acutely burned children led us to assess pain during BDC with a large 0–10 thermometer‐like scale which was well accepted and appeared to reflect the varying degrees of pain that patients experienced. Pain scores were obtained at least once each minute throughout 33 BDCs in 15 patients of 8–17 years. Plasma levels of &bgr;‐endorphin immunoactivity (iB‐EP) were measured at 5 intervals before and after BDC; mean values (± S.E.M.) ranged from 30.5 ± 4.63 pg/ml (before BDC and analgesic) to 19.2 +‐ 3.02 pg/ml (immediately following BDC). The mean pain score (MPS) for each BDC was inversely related to the iB‐EP levels of that day (P < 0.001 with 4 of the 5 iB‐EP determinations). The MPS varied directly with the extent of burn injury and inversely with weight; the 2 variables together predicted MPS as well as the iB‐EP alone (r2= 43 and 36% respectively).

Morphine-3-glucuronide: Silent regulator of morphine actions

To assess whether stoichiometric manipulation of morphine (M) metabolism can enhance analgesia or slow the development of M tolerance we co-administered M-3- glucuronide (M3G) during single or repeated doses of morphine in rats. Although M3G itself lacked analgesic activity, co-injection of M3G with M increased and prolonged analgesia beyond that seen with M. In addition, diminution of the acute analgesic effect of M after 3 once-daily doses of M did not occur after daily co-injection of M3G and M. Thus the traditional view that tolerance to the effects of M is due solely to effects mediated through opioid receptors must be broadened to include the contributions of enzyme induction or stoichiometric equilibration of M3G in this process.

Analgesic activity of a novel bivalent opioid peptide compared to morphine via different routes of administration

A novel bivalent opioid tetrapeptide, biphalin (Tyr-d-Ala-Gly-Phe-NH)2, was synthesized based on structure-activity relationships. The analgesic activity of biphalin was assessed in comparison to morphine in rats. Drugs were administered subcutaneously (s.c.), intravenously (i.v.) and intrathecally (i.t.). Tail flick and tail pinch were used as tests for analgesia. Biphalin s.c. showed negligible analgesic activity, but when given i.v. produced significant analgesia, although less potent than morphine via this route. In contrast, intrathecal biphalin was more potent than morphine. These results indicate that biphalin has intrinsic activity that is compromised by enzymatic degradation or redistribution in the periphery, properties that may render it useful in exploring analgesic actions of locally applied opioids in the periphery without the likelihood of unwanted central effects.

Management of Burn Pain in Children

In spite of the many possible methods of pain control in the burned child satisfactory pain management may still be a problem, at times formidable. The most fruitful approach would seem to be frequent assessment of pain in the individual patient with a readiness to try alternative or additional measures when relief seems inadequate. In this way the most effective analgesic agent(s), route(s), and frequency of administration, as well as nonpharmacologic methods, can be determined for each child. Among those able to speak, pain estimation is usually easily accomplished. In infants and those intubated for supported ventilation, however, the task is more difficult. Nevertheless, careful observation of physiologic signs such as heart rate and blood pressure, facial expressions, body movement and position, and the quality of an infants cries may in sum be sufficient to evaluate the intensity of pain. Monitoring of analgesic plasma levels to ascertain that they are within the ranges established for good analgesia and even determination of beta-endorphin blood levels may also aid in judging the adequacy of analgesia. By tailoring pain management methods to the needs of each child it may be possible to keep pain at acceptable levels in victims of burn injury.

Increases in plasma beta-endorphin and tail flick latency in the rat following burn injury.

In children with burn injuries we found, in earlier studies, an inverse association of plasma beta-endorphin immunoactivity (iB-EP) and pain levels. To further explore the effects of burn trauma on the peripheral release of beta-endorphin and the occurrence of centrally mediated stress analgesia, plasma iB-EP levels and tail flick latency (TFL) were measured in rats subjected (while anesthetized) to scald injury. In comparison to sham burn (dip in tepid water), burn injury increased plasma iB-EP and TFL; both the duration and magnitude of these effects were directly proportional to the extent of burns. In rats receiving no treatment, TFLs were unchanged throughout the time of the burn experiments. At 2 days post-burn TFLs were invariably back to pre-burn levels. Administration of the long-acting opioid antagonist naltrexone prior to burn injury prevented the rise in TFL. Thus the trauma of burns appeared to bring about a stress-induced analgesia (SIA). The marked increase in iB-EP during this SIA and its antagonism by naltrexone suggest that it was opioid and hormonal in character.

Enhanced potency of receptor-selective opioids after acute burn injury.

Dose-response curves of three receptor-selective opioids were established in a Group of nonburned and a group of burned rats. Morphine (p-agonist), biphalin(μ and δ agonist), and U50488H (K-agonist) were administered to each group, and analgesia was mea-sured by tail flick latency testing. Each opioid had a significant increase in potency (i.e., a decrease in EDso values) in the burned (15% body surface area) compared with the nonbumed groups. Moderate doses of each drug (i.e., EDm doses estimated from nonbumed group data) in each case augmented stress-induced analgesia in the burned group. Analgesic doses faiied to prevent a significant increase in plasma pendorphin and corticosterone after larger surface area (25%) bums. Regardless of receptor specificity, opioid analgesic potency is increased acutely after burn injuries.

Antinociception in the rat induced by a cold environment

Rats placed in a cold environment (4 degrees C) for 2 h had a sustained increase in tail flick latency (TFL) as well as an increase in tail pinch latency (TPch) that was often biphasic with an early peak response at 15 min and a later, often higher, peak at 2 h. Plasma beta-endorphin levels after a modest increase at 5 min (24%) declined throughout the remaining time in the cold. The long-acting opioid antagonist naltrexone had no effect on TFL increases but led to greater increases in TPch (P less than 0.04). In morphine-tolerant rats TFL response was the same as in controls but TPch increases were greater (P less than 0.04). Rats exposed to 2 h of cold for 17 or 18 consecutive days generally developed tolerance to the analgesia of cold, i.e. TFL and TPch increases were diminished; however, the response to morphine on day 18 was the same as in rats never exposed to cold. Adrenalectomy and hypophysectomy led to significantly smaller increases in TFL (P less than 0.02 and P less than 0.001, respectively). The TPch response in contrast, was greater in adrenalectomized (P less than 0.001) and the same in hypophysectomized rats compared to sham controls. An opioid kappa receptor antagonist (Mr 1452) given prior to cold reduced both TFL and TPch response during the first hour. Thus the analgesia induced by cold appeared to shift from an early possibly kappa opioid to a later non-opioid form. The TFL effects seemed to be under hormonal influence while the TPch were not.

Local increases of subcutaneous β-endorphin immunoactivity at the site of thermal injury

To examine interactions between exogenous opioid analgesia and endogenous opioid generation at a site of burn-induced tissue injury, we measured beta-endorphin (BE) and corticosterone (C) in aliquots of plasma and wound fluid withdrawn from subcutaneous wire mesh chambers beneath the site of a 3-5% surface area burn. After brief inhalational anesthesia at the time of thermal injury, rats received morphine (4 mg/kg, single dose), fentanyl (0.02 mg/kg hourly for 4 h), or no opioid. Systemic hormone responses and behavioral changes were minimal as expected for the minimal percentage burn. In all three groups intrachamber BE and C rose above baseline at 1, 2 and 4 h postburn, then returned to baseline at 24 h. Systemic opioid treatment produced analgesia (by tail flick latency testing) but did not reduce intrachamber hormone responses. Thus local BE and C responses at the site of thermal injury are regulated differently from systemic pituitary-adrenal responses.

Δ9-tetrahydrocannabinol and dimethylheptylpyran induced tachycardia in the conscious rat

Since cannabinoids lead to dose-related tachycardia in man but dose dependent bradycardia has been reported thus far in laboratory animals, there would seem to be a need for an experimental model in which the effect seen in man (tachycardia) could be reproduced and explored. In the conscious rat, the compounds Δ9-tetrahydrocannabinol (Δ9-THC) and dimethylheptylpyran (DMHP) injected i.p. led to dose-related increases in heart rate at 10–20 minutes after administration. In vehicle (ethanol) control rats there were small increases in heart rate. Propranolol given before Δ9-THC resulted in a parallel shift to the right of the dose-effect curve. Adrenalectomy led to a significant (p<0.01) decrease in tachycardia following Δ9-THC and DMHP while ganglionic block markedly decreased the heart rate increases after Δ9-THC (p<0.001). Systolic blood pressure at nearly all doses of Δ9-THC was minimally affected, although it tended to decrease with increasing dose. Tachycardia in the rat may be the result of a centrally mediated release of epinephrine from the adrenal gland.