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PubMed1978

Central and peripheral antialgesic action of aspirin-like drugs.

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.

Analgesics↗
PubMed1978

Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF1alpha in the rat paw.

In the rat paw prostacyclin was 5--10 times less potent than PGE2 in causing oedema, and 5 times less potent in potentiating carrageenin-induced oedema, which it did in a dose-related manner. Prostacyclin was 5 times more potent than PGE2 in producing hyperalgesia and as potent as PGE2 in restoring carrageenin-induced hyperalgesia. The effects on oedema were longer lasting than those on hyperalgesia. 6-oxo-PGF1alpha was 500 times less potent than PGE2 in causing oedema by itself and in potentiating carrageenin-induced oedema. It had no hyperalgesic activity in this test.

Animals↗
PubMed1979

Effects of prostaglandins on peripheral nociceptors in acute inflammation.

The effects of different prostaglandins were determined on (a) the hyperalgesia produced by subplantar injections of yeast given into the hind paws of weanling rats, and (b) the reflex vasopressor responses to bradykinin (BK) injected dose-arterially into the spleen of anaesthetised cats and dogs. In the rat prostaglandins (E1 greater than E2 greater than F2 alpha = F2 beta=A2=D2=I2O) injected into the same paw either with the yeast or 25 min later reduced the latency to the onset of hyperalgesia. In the cat and dog prostaglandins (E1 greater than E2 greater than F2 alpha greater than or equal to F2 beta greater than A1=A2=O) potentiated vasopressor responses to BK and reversed the inhibition of BK responses by indomethacin. It is likely that prostaglandins sensitize peripheral nociceptors through a specific prostaglandin receptor.

Acute Disease↗
PubMed1978

The hyperalgesic effects of prostacyclin and prostaglandin E2.

Hyperalgesia induced in rat paws or dog knee joints by prostacyclin (PGI2) and prostaglandin E2 was measured by a modification of the Randall-Selitto method (1) or by the degree of incapacitation (2). In both species PGI2 induced an immediate hyperalgesic effect but the effect of PGE2 had a longer latency. Low doses of PGI2 caused a short lasting effect but PGE2, large doses of PGI2 or successive administration of small doses of PGI2 caused a long lasting effect. It is suggested that prostacyclin mediates rat paw hyperalgesia induced by carrageenin. The long lasting hyperalgesic effect of PGE2 and high doses of PGI2 is possibly an indirect effect caused by stimulation of a sensory nerve sensitising mechanism.

Animals↗
PubMed1978

Early and subtle signs in low-back sprain.

The authors have previously reported myalgic hyperalgesia as a useful localizing sign in "low-back sprain" patients with no physical findings. This paper describes some other subtle signs related to the phenomenon of denervation supersensitivity which is well known to physiologists and clinicians involved in peripheral nerve disease, yet its related signs have not been applied to low-back pain. Following denervation of some neurons, muscle and peripheral receptors become supersensitive to transmitter substances and to different forms of stimuli. Since the peripheral nerve is a mixed nerve, findings are multiphasic and include autonomic dysfunction, trophic changes, cutaneous and myalgic hyperalgesia, and increased muscle tone. One or more of these signs occurred in 30 patients with secondary low-back pain but less often in 30 patients with primary or mechanical low-back pain; their presence, though slight, in asymptomatic controls may identify those individuals with a vulnerable back.

Adolescent↗
PubMed2025

CtBP1-LSD1 complex drives ErbB2 activation via H3K9me2 demethylation in DRGs during paclitaxel-induced neuropathic pain.

Paclitaxel (PTX), a commonly utilized chemotherapy drug, is linked to peripheral neuropathy, which limits dosing and significantly affects patients' quality of life. C-terminal binding protein 1 (CtBP1) is a transcriptional coregulator that participates in epigenetic gene regulation, but its role in PTX-induced neuropathic pain remains unclear. In this study, the role of CtBP1 in PTX-induced neuropathic pain is examined, with a focus on its epigenetic regulation in the dorsal root ganglia (DRGs). PTX administration markedly increased CtBP1 protein levels in DRG neurons, which coincided with the development and continuation of mechanical allodynia and thermal hyperalgesia in rat models. Our findings also revealed that CtBP1 interacts with the histone demethylase LSD1-a regulator of H3K9me2-at ErbB2 promoter sites in DRG neurons. PTX treatment increased CtBP1 protein levels, which subsequently induced LSD1 expression and decreased H3K9me2 protein levels at the ErbB2 promoter, indicating epigenetic activation of ErbB2 signaling in DRG neurons implicated in neuropathic pain. Reducing either CtBP1 or LSD1 expression reversed ErbB2 upregulation and attenuated PTX-induced pain sensitivity. These results suggest that the CtBP1-LSD1 complex epigenetically increases ErbB2 expression in DRG neurons, contributing to PTX-induced neuropathy. Targeting the CtBP1-LSD1 pathway could represent a promising therapeutic strategy for the treatment of chemotherapy-induced neuropathic pain.

Animals↗
PubMed2026

Structure-Function Analysis of the Benzyloxy Moiety of the Delta-Opioid Receptor Positive Modulator BMS-986187: Identification of a Derivative with High Selectivity for the Delta-Opioid Receptor over the Mu-Opioid Receptor In Vitro and In Vivo.

Positive allosteric modulators (PAMs) of the delta-opioid receptor (DOR) enhance endogenous opioid signaling while avoiding the convulsant liability of orthosteric agonists. However, the prototypical DOR-PAM, BMS-986187, also potentiates mu-opioid receptor (MOR) signaling, raising concerns regarding respiratory depression and abuse liability. Here, we report a structure-activity study of the benzyloxy moiety of BMS-986187 to improve selectivity for DOR over MOR, while retaining DOR-PAM potency. Fifty-two new analogues and 12 previously reported ones featuring mono- and disubstitution of the benzyl ring and phenyl-heterocycle replacements were synthesized and evaluated in β-arrestin2 recruitment assays. Ortho-substituted derivatives consistently enhanced DOR-PAM potency, although often increased MOR-PAM activity. One pyridyl derivative (compound 35) retained high DOR-PAM potency and efficacy (EC50 = 0.1 μM, Emax = 91%) with no detectable MOR activity. In mice, compound 35 enhanced DOR-mediated reversal of nitroglycerin-induced hyperalgesia, an effect absent in DOR-knockout mice, without enhancing MOR-mediated antinociception, demonstrating in vivo selectivity.

Receptors, Opioid, delta↗
PubMed2026

40 Hz light flickering alleviates chronic pain via adenosine signaling in the retina-amygdala pathway.

Chronic pain affects over 20% of the global population, yet frontline treatments remain limited in efficacy and are often hampered by serious side effects. In search of novel and effective neuromodulation alternatives, we discovered that 40 Hz flickering light effectively alleviates inflammatory and neuropathic pain in mice. We identified the retina-central amygdala (CeA) pathway as a critical conduit for the analgesic effects of 40 Hz flickering light. Using circuit-specific manipulations, we demonstrated that activation of the retina-CeA pathway is both sufficient to mimic and necessary to mediate the analgesic outcomes of 40 Hz light stimulation. In terms of mechanism, we found that 40 Hz light flickering significantly increases extracellular adenosine levels in the CeA. Local pharmacological blockade of equilibrative nucleoside transporters prevented this adenosine increase and abolished the analgesic effects of 40 Hz light flickering, whereas focal adenosine infusion phenocopied the light-induced analgesia. Both interventions required A2A receptor signaling to suppress nociceptive responses. Furthermore, we found that hyperalgesia could be destabilized in the CeA and reversed by 40 Hz light stimulation or adenosine infusion, mirroring memory reconsolidation processes and implicating the CeA as a key locus for pain memory erasure. Collectively, our findings demonstrate the multifaceted therapeutic benefits of 40 Hz light flickering as a novel non-invasive approach for pain management and reveal a distinct retina-CeA circuit and adenosine signaling mechanism for control of chronic pain and pain memory.

Animals↗
PubMed2024

Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

Animals↗
PubMed1977

Behavioral and neurochemical effects of prenatal halothane.

Permanent neurobehavioral toxicological effects have been theorized to occur at the lowest doses of a toxic agent if exposure occurs during early development compared to exposure during adulthood. Data are reviewed showing the exposure to 10 ppm of halothane from conception to day 60 of life post-partum led to adult rats (>/= 135 days of age) which were hyperalgesic to electric footshock and which committed 30% more errors learning a light-dark discrimination to escape footshock, or learning the shortest path to a food reward in a maze. Exposure only during adulthood to 10 ppm of halothane (from day 60 of life onwards) had no effects. To determine prenatal periods sensitive to halothane, rats were exposed to 12,500 ppm of halothane (with 35% oxygen) on day 3, 10, or 17 of gestation. As adults (>/= 75 days of age) day 3- and day 10-exposed rats, but not day 17-exposed rats, were hyperalgesic and committed 40% more errors in learning a visual discrimination to escape footshock. Food and water consumption, body weight, and running wheel activity were unaffected. Finally, adult rats exposed to 10, 50, or 100 ppm of halothane from conception to day 28 postpartum had 15% less 5-hydroxyindoleacetic acid in brain, but normal 5-hydroxytryptophan, noradrenalin, and dopamine. The possibility is discussed that the hyperalgesia noted above results from a permanently reduced turnover of brain serotonin produced by halothane present in brain at days 10-15 of gestation.

Abnormalities, Drug-Induced↗
PubMed1978

Transcutaneous electrical nerve stimulation in chronic pain after peripheral nerve injury.

Transcutaneous electrical stimulation was tested in 24 patients with chronic pain following a peripheral nerve injury in an extremity, in 10 patients with a good effect. All of these 10 patients displayed signs of increased sympathetic activity in addition to hyperalgesia. Sympathetic block gave complete freedeom from pain. In 14 patients with the same symptomatology but without an increased or with only very slightly increased sympathetic activity, no or an insignificant effect was obtained. Sympathetic block did not relieve the pain in this group. Transcutaneous electrical stimulation should be tried as an alternative to sympathectomy in causalgia major or minor.

Adult↗
PubMed1978

The effect of 6-hydroxydopamine on the antinociceptive action of morphine.

The role of brain catecholamines in the antinociceptive action of morphine was investigated. Intraventricular 6-hydroxydopamine which depleted brain noradrenaline in the rat had no effect on morphine's antinociceptive action but combined treatment with pargyline and 6-hydroxydopamine to further deplete brain dopamine potentiated morphine's action. It was also shown that when dopamine receptors were blocked, the antinociceptive action of morphine was potentiated whereas alpha- and beta-adrenoceptor antagonists had no effect. 6-Hydroxydopamine had two effects in mice tested on the hot-plate. It produced a hyperalgesia and antagonized the antinociceptive action of morphine. This antagonism of morphine appeared to be the result of the depletion of noradrenaline rather than dopamine. Intraventricular injection of both catecholamines restored the antinociceptive action of morphine in 6-hydroxydopamine-treated mice but dopamine was ineffective in the presence of a dopamine beta-hydroxylase inhibitor. It is suggested that the antinociceptive action of morphine is expressed by noradrenergic neurones in the mouse and by both noradrenergic and dopaminergic neurones in the rat.

Analgesics↗
PubMedDate not supplied

Response to electric shock in rats: effects of selective midbrain raphe lesions.

The forebrain serotonin (5-HT) concentrations of rats with lesions in the median (M; n equal to 5), dorsal (D; n equal to 5), and both (DM; n equal to 6) midbrain raphe nuclei were, respectively, 22, 48, and 70% lower than in control animals (n equal to 10). The lesion and control groups, however, did not evidence differences in pain sensitivity as measured by the flinch-jump technique. On the other hand, of the animals tested, those with M (n equal to 3) and DM (n equal to 4) lesions required more trials than controls (n equal to 6) to acquire a one-way avoidance response. D lesion rats (n equal to 2) did not differ from controls in one-way avoidance learning, except in terms of prolonged escape latencies during the first three trials. The previously reported increased sensitivity to painful stimuli subsequent to medial forebrain bundle lesions or para-chlorophenylalanine administration, therefore, does not appear to be due exclusively to disruption of ascending 5-HT fibers originating in the dorsal and median raphe nuclei. The effects of midbrain raphe lesions of avoidance learning, furthermore, depend on lesion locus, and are not due to either hypo- or hyperalgesia.

5,6-Dihydroxytryptamine↗
PubMed1977

Further studies on BL-3912A: effects on avoidance behavior of rats with low baselines and on reaction thresholds to electric footshock.

Rats selected for their low performance baselines in an active avoidance shuttle box task were given various doses of R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A), S-amphetamine or piracetam. BL-3912A at 1 mg/kg IP had no significant behavioral effects, while 5 and 10 mg/kg significantly increased the number of avoidance responses without affecting responses during the intertrial interval (ITI). Statistically reliable effects on behavior were not observed following 20 mg/kg of BL-3912A. S-Amphetamine at 0.5 and 1 mg/kg IP also facilitated avoidance responding, but could be differentiated from BL-3912A in that the S-amphetamine significantly increased shuttles during the ITI. S-Amphetamine at 0.1 mg/kg was not effective, while 2 mg/kg increased ITI activity. Piracetam (50 or 200 mg/kg) had no significant effects on avoidance or shuttles during ITI. Using an electric shock titration procedure, BL-3912A at 10 and 20 mg/kg IP had no significant effect on reaction thresholds. Animals receiving 100 mg/kg of p-chlorophenylalanine po for 3 days and tested 2 days later showed hyperalgesia to the electric shock. In summary, BL-3912A facilitated shuttle box avoidance responding of rats with low performance baselines. Behavioral facilitation occurred without concomitant increases in noncontingent activity or apparent changes in reactivity to electric footshock.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1979

Effects of serotonin content on pain sensitivity in the rat.

In this study the role of serotonin in pain sensitivity was investigated. Brain serotonin was elevated via low and high doses of precursor tryptophan and lowered via parachlorophenylalanine or lesions placed in the dorsal raphe nucleus. The effects on pain sensitivity were then assessed using two psychophysical pain testing procedures: (1) minimum shock intensity (threshold) which produced a conditioned escape response; and (2) total activity elicited by highly aversive inescapable shock. The results showed that only a large elevation of serotonin produced a change in escape thresholds in the direction of hypoalgesia. When total activity to a painful inescapable stimulus was evaluated only lowering of serotonin produced an effect, and this change was in the direction of hyperalgesia. The conclusion was made that serotonin does contribute to the mechanism of pain.

Animals↗
PubMed1977

Serotonin-containing neurons: their possible role in pain and analgesia.

Experimental evidence is reviewed showing that brain and spinal cord serotonergic neurons are involved in nociceptive responses, as well as in the analgesic effects of opiate narcotics. This evidence, based on studies employing pharmacological, surgical, electrophysiological, and dietary manipulations of central nervous system serotonergic neurotransmission, suggests that increases in the activity of brain and spinal cord serotonin neurons are associated with analgesia and enhanced antinociceptive drug potency, whereas decreases in the activities of these neurons correlate with hyperalgesia and diminished analgesic drug potency.

Analgesia↗
PubMed1979

Alterations in nociception and body temperature after intracisternal administration of neurotensin, beta-endorphin, other endogenous peptides, and morphine.

The antinociceptive and hypothermic effects of intracisternal administration of 11 endogenous neuropeptides and morphine were evaluated in mice. Of the substances tested, only neurotensin (NT) and beta-endorphin exerted significant antinociceptive and hypothermic effects; NT was the most potent in inducing hypothermia whereas beta-endorphin was the most potent antinociceptive agent via this route of administration. Both NT, and beta-endorphin were, on a molar basis, considerably more potent antinociceptive agents than morphine, [Met]enkephalin, or [Leu]enkephalin. NT-induced analgesia and hypothermia both were significantly dose-dependent. Substance P was found to produce significant hyperalgesia and hyperthermia. Bombesin produced a significant hypothermic effect, whereas somatostatin and luteinizing hormone-releasing hormone (luliberin) produced hyperthermia. None of the other peptides studies [bradykinin, thyrotropin-releasing factor (thyroliberin), melanocyte-stimulating hormone release-inhibiting factor (melanostatin), somatostatin, [Met]enkephalin, and [Leu]enkephalin] produced any significant alterations in colonic temperature or response to a noxious stimulus with the doses tested. These data demonstrate that NT and beta-endorphin, two endogenous brain peptides, are potent in inducing hypothermia and in producing an antinociceptive state.

Animals↗
PubMed1977

The sensitization of high threshold mechanoreceptors with myelinated axons by repeated heating.

1. Seventy high threshold mechanoreceptor units (HTMs) with myelinated axons were isolated from the sural nerves of cats and rabbits. Thirteen cat and forty-two rabbit HTMs were testec by controlled, repeated heating of the skin of the foot or lower leg to noxious levels. 2. Many of the units (77% in the cat and 40% in the rabbit) fired to heating. Only six (11%) of these fired to the first brief heating to 50-55 degrees C. The rest required 2-6 heat trials before responding. 3. Heat responding units always became more sensitive with repeated heat stimulation but their mechanical sensitivity showed no comparable changes when heat sensitization occurred. 4. If these results are applicable to man, they suggest that HTMs play little role in generating the first pain that follows skin heating but that they may be involved in the increased sensitivity to heat pain (hyperalgesia) shown by skin previously injured by heating.

Action Potentials↗