Drugs derived from cannabinoids. 7. Tachycardia and analgesia structure-activity relationships in delta9-tetrahydrocannabinol and some synthetic analogues.

delta9-Tetrahydrocannabinol (delta9-THC) and eight other synthetic analogues were found to induce a dose-related increase in heart rate in the conscious Wistar rat. Ina comparison of tachycardia with analgesic activity (mouse hot-plate and antiwrithing tests) it was found that the water-soluble ester derivatives of 2a, 1-hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo(b,d)pyran (DMHP), had the least potency for tachycardia and the greatest potency for analgesia. These findings suggest that these compounds may have promise as therapeutic agents.

Analgesic narcotic antagonists. 2. 8-Alkymorphinan-6-ones.

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

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.

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.

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.

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 infant's 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.

Dose effects of morphine and butorphanol alone and in combination after burn injury in the rat.

To test the effectiveness of analgesics after thermal trauma, butorphanol, a predominately opioid kappa-receptor agonist, and morphine, a mu-agonist, were administered alone and in combination 2 days after rats were subjected to scald burn or sham burn. After graded doses of morphine were administered, analgesia, assessed by tail flick latency and tail pinch latency, was similar in the sham-burn and scald-burn rats. With butorphanol alone analgesic effects were greater in the scald-burn than the sham-burn rats. When graded doses of butorphanol were given with a fixed dose of morphine (0.5 mg/kg), the tail pinch latency response was less in scald-burn rats and markedly less in sham-burn rats. The tail flick latency responses, however, moved in opposite directions in sham-burn and scald-burn rats receiving the drug combination: in sham-burn rats, tail flick latency effects were the same as with butorphanol alone; whereas in scald-burn rats, tail flick latency increases were suppressed except at the lowest dose.

Non-deterministic individual responses to receptor-selective opioid agonists.

To assess within a single rat strain individual variability of analgesic responses to sub-ED50 doses of receptor-selective opioids, we measured: 1) tail flick latency (TFL) responses after intrathecal (ith) injection of delta, mu, and kappa agonists administered serially; 2) TFL and tail pinch latencies (TPch) after intravenous (iv) mu and kappa agonists; and 3) TFL and TPch after iv agonists of mu or combined mu + delta selectivity. Mean values in each study confirmed an analgesic response, but individual TFL and TPch responses were chaotic and, within each study, rank order correlations between TFL and TPch values within or between drugs were insignificant. Our results suggest a hypothesis that such responses are intrinsically nondeterministic because--resembling other complex dynamic systems--they are generated by stochastic receptor-transmitter interactions that in turn evoke a series of nonlinearly coupled cellular and neural events.

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.

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 (mu-agonist), biphalin (mu- and delta-agonist), and U50488H (kappa-agonist) were administered to each group, and analgesia was measured by tail flick latency testing. Each opioid had a significant increase in potency (i.e., a decrease in ED50 values) in the burned (15% body surface area) compared with the nonburned groups. Moderate doses of each drug (i.e., ED50 doses estimated from nonburned group data) in each case augmented stress-induced analgesia in the burned group. Analgesic doses failed to prevent a significant increase in plasma beta-endorphin and corticosterone after larger surface area (25%) burns. Regardless of receptor specificity, opioid analgesic potency is increased acutely after burn injuries.

Pituitary-adrenal stress response in the absence of brain-pituitary connections.

To examine whether an acute pituitary-adrenal response to stress may occur in vivo in the absence of hypothalamic-pituitary connections, we measured plasma beta-endorphin (beta-EP) and corticosterone (C) in rats after acute thermal injury. beta-EP rose significantly after thermal injury in normal rats and rats bearing pituitary-to-kidney autotransplants but not in animals with pituitary aspiration without reimplantation. Corticosterone responses paralleled beta-EP but were significant only in normal controls. Propranolol pretreatment did not reduce postburn beta-EP and C rises in autotransplanted animals. Therefore, since circulating factors contribute in vivo to pituitary-adrenal responses, the widespread practice of using "stress hormone" responses to quantitate perioperative stress or pain may in some circumstances be flawed.

Local increases of subcutaneous beta-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.