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BACKGROUND: The increasing number of elderly patients accessing emergency departments (EDs) requires use of validated assessment tools. We compared the Identification of Seniors at Risk (ISAR), using direct patient evaluation, with the Silver Code (SC), based on administrative data. METHODS: Subjects aged 75+ years accessing a geriatric ED over an 8-month period were enrolled. Outcomes were need for hospital admission and mortality at the index ED access, ED return visit, hospitalization, and death at 6 months. RESULTS: Of 1,632 participants (mean age 84 ± 5.5 years), 75% were ISAR positive, and the sample was homogeneously distributed across the four SC risk categories (cutoffs of 0-3, 4-6, 7-10, and 11+). The two scores were mildly correlated (r = .350, p < .001) and had a similar area under the receiver-operating characteristic curve in predicting hospital admission (ISAR: 0.65, SC: 0.63) and mortality (ISAR: 0.72, SC: 0.70). ISAR-positive subjects were at greater risk of hospitalization and death (odds ratio 2.68 and 5.23, respectively, p < .001); the risk increased across SC classes (p < .001). In the 6-month follow-up of discharged patients, the tools predicted similarly ED return visit, hospital admission, and mortality. The SC predicted these outcomes even in participants not hospitalized at the index ED access. CONCLUSIONS: Prognostic stratification of elderly ED patients with the SC is comparable with that obtained with direct patient evaluation. The SC, previously validated in hospitalized patients, predicts ED readmissions and future hospitalizations even in patients discharged directly from the ED. [ABSTRACT FROM AUTHOR]

The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2) was significantly increased in cannulated (Cn) rats, compared with naive (Nv) or sham-operated (Sh) rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%). The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

Objectives: Converging evidence indicates that Horticultural Therapy (HT) contributes to significant reductions in stress, loneliness, and depression, notable risk factors for suicidality. This pilot study aimed to assess the initial feasibility and acceptability of HT when virtually administered., Intervention: Telehealth-delivered horticultural therapy (TeleHT) was administered to groups of Veterans, including those with elevated suicide risk over the course of four weeks. Participants were each sent a package through the mail of at-home gardening supplies that were used to facilitate multisensory, nature experiences during weekly HT sessions administered via Zoom., Outcome Measures: Participants completed thermometer-based scales for the suicide risk factors of stress, loneliness, depression, and pain before and after each TeleHT session. Post-intervention qualitative assessments were completed upon the conclusion of the four-week intervention., Results: Significant reductions in stress, depression, and loneliness risk were observed from weekly pre- to post-session measures (p < 0.05), with 89.1 % HT completion rate. Stress, pain, depression, and loneliness indices also showed small to medium sized symptom reduction amongst Veterans with no history of suicidality (Cohen's d=-0.70, d=-0.49, d=-0.62, d=-0.71), while those with elevated suicide risk at baseline also showed reduction in these risk factors with small to medium effect sizes (d=-0.58, d=-.018, d=-0.46, d=-0.41). Qualitative post-intervention assessments indicated a high degree of acceptability and pointed to the inclusion of mailed gardening packages as particularly relevant to positive experiences., Conclusions: While future work is needed to fully assess efficacy, findings from this pilot study demonstrate an initial feasibility and acceptability through a high retention rate and positive qualitative assessments for TeleHT that mirror that of the in-person intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

A 4-year-old female patient presents to the pediatric emergency department with acute onset of ataxia and occipital headache. Initial investigation, including computed tomography imaging, failed to demonstrate any focal neurologic lesion. Subsequent studies, however, reveal an acute thrombosis of the superior cerebellar artery. Further work up identified the likely causative factor to be a heterozygous mutation at the methylene tetrahydrofolate reductase gene. In this case report, we will discuss the work-up of pediatric ataxia, the evaluation and management of cerebrovascular accidents in children, and the association between stroke and mutation of the methylene tetrahydrofolate reductase gene.

The effect of interleukin-13 (IL-13) on hyperalgesic responses to intraplantar (i.pl.) injection of carrageenin, E. coli endotoxin (LPS), bradykinin, tumour necrosis factor a (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8) and prostaglandin E(2) (PGE(2)) was investigated in a model of mechanical hyperalgesia in rats. Also, the cellular source of the IL-13 was investigated. IL-13, administered 30 min before the stimulus, inhibited responses to carrageenin, LPS, bradykinin, and TNF-alpha, but not responses to IL-1 beta, IL-8 and PGE2. IL-13, administered 2 hours before the injection of IL-1b, did not affect the response to IL-1b, whereas IL-13, administered 12 hours or 12 + 2 hours before the IL-1 beta, inhibited the hyperalgesia (- 35%, - 77%, respectively). In murine peritoneal macrophages, IL-13 administered 2 hours before stimulation with LPS, inhibited the production of IL-1 beta (- 67%) and PGE(2) (- 56%). IL-13 administered 12 hours before stimulation with LPS inhibited LPS-stimulated PGE(2) but not IL-1 beta. An anti-IL-13 serum potentiated responses to carrageenin, LPS, bradykinin and TNF-alpha (but not IL-1 beta and IL-8), as well as responses to bradykinin in rats depleted of mast cells with compound 40/80, but not in athymic rats. These data suggest that IL-13, released by lymphocytes, limits inflammatory hyperalgesia by the inhibition of the production TNF-alpha, IL-1 beta, IL-8 and PGs.

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin + atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+ a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 microg) was inhibited by DALBK or HOE 140 and abolished by DALBK + HOE 140. The hyperalgesic response to LPS (5 microg) was not antagonized by DALBK + HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude.

1. The effect of interleukin-10 (IL-10) upon the hyperalgesic activities in rats of bradykinin, tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and carrageenin were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to bradykinin (1 micrograms) were inhibited in a dose-dependent manner by prior treatment with IL-10 (1-100 ng). 3. Hyperalgesic responses to TNF alpha (2.5 pg), IL-1 beta (0.5 pg) and IL-6 (1.0 ng) but not to IL-8 (0.1 ng) and PGE2 (50 ng and 100 ng) were inhibited by prior treatment with IL-10 (10 ng). 4. Hyperalgesic responses to carrageenin (100 micrograms) were inhibited by IL-10 (10 ng) when this cytokine was injected before but not after the carrageenin. 5. A monoclonal antibody to mouse IL-10 potentiated the hyperalgesic responses to carrageenin (10 micrograms) and TNF alpha (0.025 pg) but not that to IL-8 (0.01 ng). 6. In in vitro experiments in human peripheral blood mononuclear cells (MNCs), IL-10 (0.25-4.0 ng ml-1) inhibited in a dose-dependent manner PGE2 production by MNCs stimulated with IL-1 beta (1-64 ng ml-1) or endotoxin (lipopolysaccharide, LPS, 1 iu = 143 pg ml-1) but evoked only small increases in IL-1ra production. 7. These data suggest that IL-10 limits the inflammatory hyperalgesia evoked by carrageenin and bradykinin by two mechanisms: inhibition of cytokine production and inhibition of IL-1 beta evoked PGE2 production. Our data suggest that the latter effect is not mediated via IL-10 induced IL-Ira and may result from suppression by IL-10 of prostaglandin H synthase-2 (COX-2).

1. The oral administration of a benzothiazolinone derivative (benzoyl-6 dihydro-2,3 benzothiazole), S14080, caused dose-dependent antinociception in the rat paw pressure test, which represents a model of mechanical hyperalgesia. S14080 had no significant effect on the inflammatory oedema induced by carrageenin or on the tail flick test, nor did it possess a notable antipyretic effect. 2. Post-treatment with S14080 dose-dependently antagonized the hyperalgesia induced by prostaglandin E2, bradykinin, dopamine and by the hyperalgesic cytokines reported to be released by carrageenin (tumour necrosis factor alpha, interleukin-1 and interleukin-8). 3. The blockade of prostaglandin E2-induced paw hyperalgesia by oral pretreatment of the rats with S14080 was abolished by prior intraplantar administration of either naloxone or NorBNI which are non-specific and specific kappa opioid antagonists, respectively. 4. Adrenalectomy abolished the oral antinociceptive effect of S14080. 5. Five consecutive daily injections of S14080 did not produce tolerance such as that seen with the central antinociceptive action of morphine. 6. As with peripherally acting opiates, the antinociceptive activity of S14080 was abolished by the intraplantar injection of agents which inhibit either arginine synthetase (NG-monomethyl-L-arginine) or the activation of guanylate cyclase (methylene blue). 7. We conclude that S14080 is a new type of peripheral antinociceptive which, in rats, acts mainly by releasing an endogenous, opioid-like substance from the adrenal glands.

In the present investigation we have tested the hypothesis that spinal glutamate release by inflammatory stimuli causes hyperalgesia through sensitization of the primary sensory neurons associated with nociception. In these experiments, the rat paw hyperalgesia pressure test in which inflammatory hyperalgesia is blocked by the intraplantar administration of morphine (MPH) or SNAP, a NO donor was used. Glutamate and glutamatergic ionotropic agonists such as NMDA or AMPA injected intrathecally (i.t.) caused a dose-dependent hyperalgesia. Quisqualate or ACPD, both of which are glutamate metabotropic receptor agonists, had no hyperalgesic effect. The hyperalgesic response to glutamate and NMDA injected i.t. was antagonized by the intraplantar (i.pl.) injection of either MPH or SNAP. This observation indicates that the hyperalgesia induced by glutamate acting through an NMDA pre-synaptic receptor causes sensitization of the primary sensory neurons. Confirming that the analgesia by i.pl. injection of SNAP or MPH was due to an action in primary peripheral sensory neurons, it was shown that pretreatment of the paws with methylene blue (MB, an inhibitor of guanylate cyclase) or with MB and L-NMMA (an inhibitor of NO synthase) abolished their respective analgesic effect. AMPA i.t. induced hyperalgesia was not inhibited by either i.pl. administration of MPH or SNAP, indicating that its hyperalgesic capacity results from an action at a site other than the primary sensory neuron.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The hyperalgesic activities in rats of bradykinin, carrageenin and lipopolysaccharide (LPS) were investigated in a model of mechanical hyperalgesia. 2. Bradykinin and carrageenin evoked dose-dependent hyperalgesia with maximum responses of similar magnitude to responses to LPS (1 and 5 micrograms). 3. Hoe 140, an antagonist of BK2 receptors, inhibited in a dose-dependent manner hyperalgesic responses to bradykinin, carrageenin and LPS (1 microgram) but not responses to LPS (5 micrograms), prostaglandin E2, dopamine, tumour necrosis factor alpha (TNF alpha), IL-1, IL-6 and IL-8. 4. Responses to bradykinin and LPS (1 and 5 micrograms) were inhibited by the cyclo-oxygenase inhibitor, indomethacin and by the beta-adrenoceptor antagonist, atenolol. The effects of indomethacin and atenolol were additive: their combination abolished responses to bradykinin and LPS (1 microgram) and markedly attenuated the response to LPS (5 micrograms). 5. Antiserum neutralizing endogenous TNF alpha abolished the response to bradykinin whereas antisera neutralizing endogenous IL-1 beta, IL-6 and IL-8 each partially inhibited the response. The combination of antisera neutralizing endogenous IL-1 beta+IL-8 or IL-6+IL-8 abolished the response to bradykinin. 6. Antisera neutralizing endogenous TNF alpha, IL-1 beta, IL-6 and IL-8 each partially inhibited responses to LPS (1 and 5 micrograms). Increasing the dose of antiserum to TNF alpha or giving a combination of antisera to IL-1 beta+IL-8 or IL-6+IL-8 further inhibited responses to LPS (1 and 5 micrograms). 7. These data show that bradykinin can initiate the cascade of cytokine release that mediates hyperalgesic responses to carrageenin and endotoxin (1 microgram). The lack of effect of Hoe 140 on hyperalgesic responses to LPS (5 microgram) suggests that the release of hyperalgesic cytokines can be initiated independently of bradykinin BK2 receptors.

1. The hyperalgesic activities in rats of interleukin-1 beta (IL-1 beta), IL-6, IL-8, tumour necrosis factor alpha (TNF alpha) and carrageenin were investigated. 2. IL-6 activated the previously delineated IL-1/prostaglandin hyperalgesic pathway but not the IL-8/sympathetic mediated hyperalgesic pathway. 3. TNF alpha and carrageenin activated both pathways. 4. Antiserum neutralizing endogenous TNF alpha abolished the response to carrageenin whereas antisera neutralizing endogenous IL-1 beta, IL-6 and IL-8 each partially inhibited the response. 5. The combination of antisera neutralizing endogenous IL-1 beta + IL-8 or IL-6 + IL-8 abolished the response to carrageenin. 6. These results show that TNF alpha has an early and crucial role in the development of inflammatory hyperalgesia. 7. The delineation of the role of TNF alpha, IL-1 beta, IL-6 and IL-8 in the development of inflammatory hyperalgesia taken together with the finding that the production of these cytokines is inhibited by steroidal anti-inflammatory drugs provides a mechanism of action for these drugs in the treatment of inflammatory hyperalgesia.

We tested the hypothesis that activation of the nitric oxide (NO)-cGMP pathway is involved in the mechanism of two directly acting non-opiate peripheral analgesics, myrcene and dipyrone, using our modification of the Randall-Selitto test. The NO inhibitor, NG-monomethyl-L-arginine (50 micrograms/paw) and methylene blue (500 micrograms/paw) abolished the analgesic effect of dipyrone and myrcene. Dibutyryl cyclic adenosine monophosphate (DbcAMP) caused a dose-dependent hyperalgesia (20, 50 and 100 micrograms/paw). Only responses to low doses of DbcAMP were inhibited by the two analgesics. Pretreatment with MY5445 (50 micrograms/paw) resulted in potentiation of the effects of both analgesics. These results support our hypothesis that the sensitivity of nociceptors may be controlled by the balance between the levels of cAMP and cGMP. Stimulation of the NO-cGMP pathway is probably the common denominator for the mode of action of peripheral analgesics which block hyperalgesia directly.

Surprisingly, a single topical application of a nitroglycerin (NTG) gel in humans has been shown to cause analgesia and to reduce oedema in thrombophlebitis. In the present investigation, we showed that the NTG gel reduces prostaglandin E2-induced hyperalgesia and blocks neurogenic inflammation induced in rat skin by antidromic electrical stimulation of the saphenous nerve. These results offer an explanation for the effects of topical application of NTG observed in thrombophlebitis, which may be common to other cutaneous pathologies. The data also support the development of nitrates the effects of which are restricted to the site of application.

1. The hyperalgesic effects of interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2) were measured in rats. 2. Hyperalgesic responses to IL-1 beta were inhibited in a dose-dependent manner by alpha-melanocyte stimulating hormone (alpha-MSH)-related peptides with the following order of potency: [N1(4),D-Phe7]alpha-MSH greater than alpha-MSH greater than Lys-D-Pro-Val greater than Lys-Pro-Val greater than Lys-D-Pro-Thr greater than D-Lys-Pro-Thr. 3. Hyperalgesic responses to PGE2 were not inhibited by Lys-D-Pro-Thr and D-Lys-Pro-Thr but were inhibited in a dose-dependent manner by the other peptides with the same order of potency as against IL-1 beta. 4. The potencies of [N1(4), D-Phe7]alpha-MSH and alpha-MSH were greatly diminished by deletion of their C-terminal tripeptide, Lys11-Pro-Val13. 5. Nor-binaltorphimine (Nor-BNI) largely reversed the analgesic effects of alpha-MSH, [N1(4), D-Phe7]alpha-MSH, Lys-Pro-Val and Lys-D-Pro-Val indicating that kappa-opioid receptors mediated the analgesic activity of these peptides. 6. Nor-BNI did not antagonize the inhibition by Lys-D-Pro-Thr and D-Lys-Pro-Thr of IL-1 beta evoked hyperalgesia indicating that these peptides were not acting via kappa-opioid receptors.

1. The hyperalgesic effects of interleukin-8 (IL-8), interleukin-1 beta (IL-1 beta) and carrageenin were measured in a rat paw pressure test. 2. IL-8 evoked a dose-dependent hyperalgesia which was attenuated by a specific antiserum, the beta-adrenoceptor antagonists atenolol and propranolol, the dopamine receptor antagonist SCH 23390 and the adrenergic neurone-blocking agent guanethidine. The hyperalgesia was not attenuated by the cyclooxygenase inhibitor indomethacin or the IL-1 beta analogue Lys-D-Pro-Thr. 3. IL-1 beta-evoked hyperalgesia was attenuated by indomethacin and Lys-D-Pro-Thr but not by atenolol or SCH 23390. 4. Carrageenin-evoked hyperalgesia was attenuated by atenolol, indomethacin and anti-IL-8 serum. The effects of atenolol and anti-IL-8 serum were not additive. The effects of indomethacin and anti-IL-8 serum were additive: this combination abolished carrageenin-evoked hyperalgesia. 5. A new biological activity of IL-8 is described, namely the capacity to evoke hyperalgesia by a prostaglandin-independent mechanism. IL-8 is the first endogenous mediator to be identified as evoking hyperalgesia involving the sympathetic nervous system. Since IL-8 is released by activated macrophages and endothelial cells it may be a humoral link between tissue injury and sympathetic hyperalgesia.

Oral administration of an infusion of lemongrass (Cymbopogon citratus) fresh leaves to rats produced a dose-dependent analgesia for the hyperalgesia induced by subplantar injections of either carrageenin or prostaglandin E2, but did not affect that induced by dibutyryl cyclic AMP. These results indicate a peripheral site of action which was confirmed with the essential oil obtained by steam distillation of the leaves. Silica gel column fractionation of the essential oil allowed the identification of myrcene as the major analgesic component in the oil. Identification of the components was made by thin-layer chromatography and checked by mass spectrometry. The peripheral analgesic effect of myrcene was confirmed by testing a standard commercial preparation on the hyperalgesia induced by prostaglandin in the rat paw test and upon the contortions induced by intraperitoneal injections of iloprost in mice. In contrast to the central analgesic effect of morphine, myrcene did not cause tolerance on repeated injection in rats. This analgesic activity supports the use of lemongrass tea as a "sedative" in folk medicine. Terpenes such as myrcene may constitute a lead for the development of new peripheral analgesics with a profile of action different from that of the aspirin-like drugs.

We have previously described the peripheral analgesic effect of dibutyryl cyclic GMP, acetylcholine (ACh) and morphine (Mph) injected into the rat paws. Since ACh induces nitric oxide (NO) release from endothelial cells which is though to stimulate guanylate cyclase (GC) we investigated if NO-cyclic GMP pathway was involved in the analgesia by those agents. Using a modification of the Randall-Selitto rat paw test, it was found that sodium nitroprusside, which releases NO non-enzymatically, blocked rat paw PGE2 induced hyperalgesia. The peripheral analgesic effect of sodium nitroprusside, ACh and morphine was enhanced by intraplantar injection of an inhibitor of cyclic GMP phosphodiesterase (MY5445) and blocked by a GC inhibitor, methylene blue (MB). Peripheral analgesia induced by ACh and morphine, but not by sodium nitroprusside, was blocked by NG-monomethyl-L-arginine (L-NMMA) an inhibitor of the formation of NO from L-arginine. Central effect of morphine as tested by the rat paw and by the tail flick tests was inhibited by intraventricular injection of methylene blue. In addition, the central morphine analgesia was potentiated by My5445. In contrast, with the periphery, the central effect of morphine was not blocked by L-NMMA. Our results demonstrate that NO causes peripheral analgesia via stimulation of GC and supports the suggestion that at this site morphine and acetylcholine analgesia is subsequent to NO release. In the mechanism of the central analgesic effect of morphine, the cGMP system is activated but via NO release, probably by a direct stimulation of the receptors. This is the first demonstration that links peripheral and central analgesic effect of morphine to the stimulation of GC system.

Ammonium salt derivatives of natural allylphenols were synthesized with the purpose of obtaining potential peripheral analgesics. These drugs, by virtue of their physicochemical properties, would not be able to cross the blood brain barrier. Their inability to enter into the central nervous system (CNS) should prevent several adverse effects observed with classical opiate analgesics (Ferreira et al., 1984). Eugenol (1) O-methyleugenol (5) and safrole (9) were submitted to nitration, reduction and permethylation, leading to the ammonium salts 4, 8 and 12. Another strategy applied to eugenol (1), consisting in its conversion to a glycidic ether (13), opening the epoxide ring with secondary amines and methylation, led to the ammonium salts 16 and 17. All these ammonium salts showed significant peripheral analgesic action, in modified version of the Randall-Sellito test (Ferreira et al., 1978), at non-lethal doses. The ammonium salt 8 showed an activity comparable to that of methylnalorphinium, the prototype of an ideal peripheral analgesic (Ferreira et al., 1984).

We have previously described the analgesic effect of dibutyryl cyclic GMP or acetylcholine (ACh) injected into rat paws. Since ACh induces nitric oxide (NO) release from endothelial cells, we investigated the possible involvement of the NO-cyclic GMP pathway in ACh-induced analgesia, using a modification of the Randall-Selitto rat paw test. We found that sodium nitroprusside, which releases NO non-enzymatically, caused antinociception in the rat paw made hyperalgesic with prostaglandin E2. The analgesic effect of sodium nitroprusside and ACh was enhanced by intraplantar injection of an inhibitor of cyclic GMP phosphodiesterase (MY 5445) and was blocked by a guanylate cyclase inhibitor, methylene blue (MB). The analgesia induced by ACh, but not by sodium nitroprusside, was blocked by NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine. L-arginine itself had little or no effect upon prostaglandin-induced hyperalgesia but caused significant analgesia in paws inflamed with carrageenin. This analgesia was blocked by MB, as well as by L-NMMA, and was potentiated by MY 5445. These results suggest that ACh-induced analgesia was mediated via the release of NO. The results also indicate that the guanylate cyclase system is stimulated in the inflammatory reaction. The analgesia resulting from activation of this system is possibly overshadowed by substances that concomitantly stimulate nociceptor hyperalgesic mechanisms.

The peripheral and central effects of some non-steroid anti-inflammatory drugs, aspirin, indomethacin, paracetamol and phenacetin were studied by comparing their intraplantar and intracerebroventricular effects on hyperalgesia induced by carrageenin injected into the rat paw. Hyperalgesia was measured by a modification of the Randall-Selitto test. The agents tested had antialgesic effects when given by any route. Their intraventricular administration enhanced the antialgesic effect of anti-inflammatory drugs administered into the paw. Previous treatment of one paw with carrageenin reduced the oedema caused by a second injection of carrageenin in the contralateral paw. In contrast, it had no effect on the intensity of hyperalgesia but shortened the time necessary for it to reach a plateau. Administration of a prostaglandin antagonist (SC-19220) in the cerebral ventricles, in the rat paw or in both sites, significantly inhibited the hyperalgesia evoked by carrageenin. The maximal hyperalgesic effect of intraplantar injections of prostaglandin E2 could be further enhanced by its cerebroventricular administration. It was suggested that carrageenin hyperalgesia has a peripheral and a central component and that the cyclo-oxygenase inhibitors used may exert an antialgesic effect by preventing the hyperalgesia induced by a peripheral and/or central release of prostaglandins.

Oral methylnalorphine ( methylnalorphinium ) caused a dose-dependent selective inhibition of inflammatory hyperalgesia (measured in the rat by a modified version of the Randall- Selitto test) without affecting the oedema. When subcutaneously injected, repeated doses of morphine for 5 days caused progressive analgesic tolerance. Tolerance was not observed after similar treatment with methylnalorphinium or methylmorphinium . Animals displaying analgesic tolerance to systemic morphine did not exhibit tolerance to the local ( intraplantar ) injection of morphine, methylnalorphinium or methylmorphinium . In contrast with nalorphine and other opiates, methylnalorphinium did not reduce intestinal transit in mice. Methylnalorphinium , a mixed opiate agonist-antagonist devoid of central effects, might be considered the prototype of an ideal peripheral analgesic since it was orally active, did not affect intestinal transit and did not cause analgesic tolerance.

1. Lysis of rat thioglycolate-stimulated peritoneal macrophages releases a low molecular weight factor (0.5 less than MW less than 10 kD) into the supernatant. Bilateral hyperalgesia was observed when this factor, denoted macrophage hyperalgesic factor (MHF), was injected into one hind paw or into the peritoneal cavity of the rat. 2. Similar activity was detected in stimulated peritoneal and tumoral mouse macrophages (J774G8) but not in lysates of rat exudate neutrophils or in peritoneal resident (non-stimulated) macrophages. 3. The hyperalgesia induced by MHF was abolished by local intraplantar injection of indomethacin, thus suggesting a peripheral release of cyclo-oxygenase products. This suggestion was supported by the ability of MHF to release prostaglandin-like material when added to a guinea pig lung perfusate. 4. Peritonitis induced by the administration of carrageenin caused concomitant bilateral rat paw hyperalgesia and an MHF-like activity was demonstrable in peritoneal exudate 30 min after the carrageenin insult. 5. Purified human interleukin-1 (IL-1) given locally or systemically also produced bilateral hind paw hyperalgesia which was abolished by local administration of indomethacin. The possibility that MHF may be a fragment of IL-1 is discussed.

The prostaglandin hyperalgesia and tail immersion tests were used to evaluate the analgesic action of morphine, codeine, d-propoxyphene and pentazocine following intraperitoneal, intraplantar and intracerebroventricular administration to rats. In the prostaglandin hyperalgesia test, all drugs produced a dose-dependent analgesia by the various routes. The rank order of potency after intraperitoneal administration was morphine (100) greater than d-propoxyphene (4) greater than pentazocine (2) greater than codeine (1). Although morphine (ID50 = 4 micrograms) was a very potent analgesic when given intracerebroventricularly, very shallow dose-response curves were obtained with the other substances which promoted less than 30% of inhibition at doses up to 250 micrograms. In the paw, morphine (ID50 = 5 micrograms) was only 5-8 times more potent than pentazocine, propoxyphene and codeine. Thus, in contrast with morphine, intraplantar administration of codeine, pentazocine and d-propoxyphene is much more effective than intracerebroventricular administration. In the tail immersion test the smallest intraperitoneal doses which affected the reaction time were 9 mg/kg morphine, 16.2 mg/kg codeine and pentazocine and 48.6 mg/kg d-propoxyphene. When injected intracerebroventricularly morphine (10 micrograms) was the only opiate that caused a detectable analgesic effect. In the prostaglandin hyperalgesia test, a small dose of naloxone (1 micrograms) given into the rat paw significantly antagonized the analgesic effect of d-propoxyphene, codeine and pentazocine administered either intraperitoneally or intraplantarly. These results clearly indicate that a method involving or mimicking inflammatory hyperalgesia is much more sensitive in detecting opiate analgesia than a method which uses heat as a nociceptive stimulus. Furthermore, our results support the proposition that part of the overall analgesia which follows the systemic administration of opiates is due to a peripheral antinociceptive action.

1. The effects of N-methyl morphine and N-methyl nalorphine were studied on the hyperalgesia induced by prostaglandin E2 in the rat paw. Morphine and N-methyl morphine injected intraperitoneally (2-8 mg/kg) caused a dose-dependent analgesia. The potency of N-methyl morphine was of the same order of magnitude as its parent compound in causing analgesia. 2. Nalorphine caused a short-lasting analgesia followed by an enhancement of prostaglandin-induced hyperalgesia. In contrast, its analogue, N-methyl nalorphine, injected intraperitoneally, induced analgesia but did not enhance the hyperalgesia induced by prostaglandin E2 or induce hyperalgesia in the control paw. 3. Treatment of the animals with N-methyl nalorphine at a dose which had no apparent analgesic effect antagonized the analgesic effect of morphine or N-methyl morphine. 4. Administration of a low dose of N-methyl nalorphine into the paw totally antagonized the analgesic effect of N-methyl morphine administered either locally into the paw, or intraperitoneally. 5. It is concluded that quaternary analogues of morphine and nalorphine, which do not have central effects because they do not cross the blood-brain barrier, retain the peripheral analgesic effects of the parent compounds.

Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.) than oedema (180 mg/kg, i.p.) Dipyrone administered intraperitonially or intraplantarly was able to antagonise PGE2-, isoprenaline- and calcium chloride-induced hyperalgesia, effects which are not observed with non-steroid anti-inflammatory drugs. Systemic or local administration of dipyrone had no effect upon Db-cAMP-induced hyperalgesia while a centrally acting analgesic, morphine, given systemically, was highly effective. These results support our suggestion that the mechanism of action of dipyrone is different from that of classical non-steroidal anti-inflammatory drugs. Although the site of action is peripheral its analgesic effect does not derive from inhibition of the synthesis of prostaglandins but is exerted via direct blockade of the inflammatory hyperalgesia.

Interleukin-1 (IL-1) describes two inflammatory proteins, IL-1 alpha and IL-1 beta, produced by activated macrophages and other cell types and encoded by two genes. Their amino acid sequences have only 26% similarity, but their biological activities are comparable, with a few exceptions; indeed, both molecules appear to act at the same receptor. As IL-1 release prostaglandins which sensitize nociceptors in man and in experimental animals, we tested IL-1 alpha and IL-1 beta in rats for hyperalgesic (nociceptive) activity. Our results show that IL-1 beta given systemically is an extremely potent hyperalgesic agent with a probable peripheral site of action; IL-1 alpha is approximately 3,000 times less active than IL-1 beta. We have delineated the region of IL-1 beta mediating the hyperalgesic effect and developed an analgesic tripeptide analogue of IL-1 beta which antagonizes hyperalgesia evoked by IL-1 beta and by the inflammatory agent carrageenan.

Prostaglandin E2, prostacyclin and Db-cAMP injected into the rat paw induce hyperalgesia. This hyperalgesic effect of the prostaglandins but not of Db-CAMP was blocked by pre-treatment of the animals with cycloheximide. Prostaglandin hyperalgesia thus seems to be dependent on the triggering of some metabolic process which enhances the effects of physical or chemical stimuli.