The Role of Adrenocorticotropic Hormone in the Inhibition of Pain Reactions in Conscious Rats

Experiments on conscious male Sprague–Dawley rats were performed to study the effects of adrenocorticotropic hormone (ACTH) on pain reactions. Pain sensitivity was assessed in terms of the latent period of tail withdrawal in response to heat. Systemic administration of ACTH and glucocorticoids to animals with normal levels of hormone production led to increases in the latent period of the tailflick reaction. The roles of glucocorticoids and opioid peptides in ACTH-induced analgesia were addressed in experiment on animals with deficient glucocorticoid production and animals in which opiate receptors were blocked with naltrexone. Deficiency in glucocorticoid production had no effect on ACTH-induced increases in the latent period of the tailflick reaction, while blockade of opiate receptors completely eliminated this effect of ACTH. ACTH-induced analgesia in conscious rats is mediated by opiate receptors and not by glucocorticoids.     

Mechanisms of the Effects of Adrenocorticotropic Hormone on Pain Sensitivity in Rats

Experiments on anaesthetized male Sprague-Dawley rats were performed to study the effects of adrenocorticotropic hormone (ACTH) on pain sensitivity. Systemic administration of ACTH to animals with normal hormone production induced rapidly developing (starting at 3 min) and prolonged (30 min) increases in pain response thresholds. Blockade of opiate receptors led to suppression of the initial stage of the analgesic effect of ACTH: the response was seen only from 15 to 30 min. In animals with deficient glucocorticoid production, the duration of the analgesic action of ACTH decreased to 15 min. Analgesia was completely eliminated by the combination of suppression of glucocorticoid production and blockade of opiate receptors. The analgesic effect of ACTH was mediated by two mechanisms: 1) a rapidly-acting (from 3 to 15 min) mechanism associated with opiate receptors and not related to glucocorticoids, and 2) a delayed (from 15 to 30 min) mechanism associated with glucocorticoids but not opiate receptors.     

Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic responses in the formalin test in mice

The present study examined the interaction between mazindol (MZ), an anorectic drug extensively used in Brazil and opioid/non-opioid endogenous analgesic systems activated by swim-stress. Further, the role of opioid, dopamine and N-methyl-D-aspartate (NMDA) receptors in mediating the analgesic effect was evaluated. The stress-induced analgesia of a 3-min swimming at 32 degrees C (opioid/non-opioid) and 20 degrees C (non-opioid) were assessed using the formalin test. Male Swiss mice were intraperitoneally injected with naloxone (1.0 mg/kg), sulpiride (3.0 mg/kg), MK-801 (0.075 mg/kg) or saline/vehicle 15 min prior, and with MZ (0.5 mg/kg) or saline/vehicle 5 min prior to swimming. The dose of MZ (0.5 mg/kg) did not cause analgesic effect, however, the association of MZ and swim-stress at both temperatures displayed synergistic interaction on analgesia that was blocked by sulpiride and MK-801 but not by naloxone. The present results suggest that MZ and swim-stress acted synergistically on analgesic responses, involving mainly the non-opioid component and possibly mediated by dopamine D2 receptors and NMDA receptors.     

Anger Regulation Style, Postoperative Pain, and Relationship to the A118G Mu Opioid Receptor Gene Polymorphism: A Preliminary Study

Greater trait anger-out is associated with elevated pain responsiveness. Previous work suggests this effect may be mediated by deficient endogenous opioid analgesia, possibly reflecting diminished opioid receptor sensitivity. The A118G single nucleotide polymorphism (SNP) of the mu opioid receptor gene influences both opioid receptor sensitivity and clinical responsiveness to opioid analgesics. Therefore, this study tested whether this SNP either mediated or moderated the effects of anger-out on postsurgical pain outcomes. Forty-eight patients undergoing coronary artery bypass graft surgery provided genetic samples, and completed measures of anger-out and postsurgical pain. Postsurgical opioid analgesic use was also recorded. Anger-out was positively associated with postsurgical pain ratings (p < 0.05). Anger-out was not associated with A118G SNP status (p > 0.10), suggesting the latter is unlikely to mediate anger-out's pain-related effects. A significant anger-out × A118G interaction was observed on analgesic use (p < 0.05), due to a much stronger positive relationship between anger-out and analgesic demands in patient with the A118G SNP (b = 0.53) than those with the wild-type receptor (b = 0.07). These results suggest that the A118G SNP may moderate but not mediate the effects of anger-out on postoperative pain responses.     

Are the analgesic effects of social defeat mediated by benzodiazepine receptors?

Social conflict in mice is associated with at least two forms of analgesia. A long-lasting opioid reaction is evident in intruder mice exposed to prolonged attack, whilst an acute non-opioid analgesia is seen in response to either defeat experience per se or the territorial scent-marking of an aggressive conspecific. Recent work from this laboratory has suggested that the non-opioid analgesic reaction to defeat experience may be mediated via benzodiazepine receptor mechanisms. The present studies were designed to further test this tentative hypothesis. Results confirmed that defeat analgesia is dose-dependently blocked by Ro15-1788 (20-40 mg/kg) and diazepam (2-4 mg/kg), and also indicated partial antagonism of the reaction by CGS8216 (2.5 mg/kg). The partial agonists CGS9896 (2.5-20 mg/kg) and ZK91296 (2.5-20 mg/kg) were ineffective in blocking the reaction, a finding also obtained with the full agonist ZK93423 (0.05-10 mg/kg). However, the antagonist/weak inverse agonist ZK93426 was found to possess significant intrinsic analgesic activity (10 mg/kg) and to enhance defeat analgesia (5-10 mg/kg). Although several interpretative frameworks for the current pharmacological profile are considered, it is concluded that full clarification of the substrates of defeat analgesia must await further investigations.     

促肾上腺皮质激素对慢性痛大鼠痛行为和海马内BDNF、CRF水平的影响

目的与方法:采用痛行为评分方法、免疫组化和原位杂交技术,观察促肾上腺皮质激素(ACTH)对完全福氏佐剂所致的关节炎大鼠海马内脑源性神经营养因子(BDNF)及其功能性受体trkB和促肾上腺皮质激素释放激素(CRH)水平的影响。结果:关节炎大鼠的痛行为评分显著高于正常对照组,同时注射侧对侧海马内BDNF免疫活性(IR)神经元、CRHmRNA阳性神经元和BDNF/CRHmRNA双染神经元数在注射佐剂后 2 4h显著高于正常对照组,而腹腔注射ACTH(2 5IU/kg或 12 5IU/kg)后,上述指标显著低于关节炎组;摘除双侧肾上腺后,腹腔注射ACTH的关节炎大鼠对侧海马内BDNF-IR、CRHmRNA阳性神经元和BDNF/CRHmRNA双染神经元数明显高于未摘除肾上腺的关节炎组。结论:海马内的BDNF和CRH参与慢性痛的调制,ACTH能抑制海马内BDNF和CRH的升高而产生镇痛作用,肾上腺对ACTH发挥其功能起决定性作用.     

Effect of ACTH on Pain Sensitivity in Rats

Systemic administration of ACTH to rats with normal hormone production induced a rapid (started 3 min postinjection) and long-term (persisted 30 min) elevation of pain threshold. Complete inhibition of glucocorticoid production shortened the duration of ACTH-induced analgesia to 15 min. The biphasic effect of ACTH on pain sensitivity is probably mediated by short-term glucocorticoid-independent and long-term glucocorticoid-dependent mechanisms.     

Carcinoid tumors of the thymus and Cushing's syndrome: Clinicopathologic features and current best evidence regarding the cell of origin of these unusual neoplasms

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET.The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p < 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas.The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.     

The role of the hormones of the hypothalamo-hypophyseal-adrenocortical system in the analgesic effect of corticotropin-releasing hormone

Experiments on anesthetized male rats were performed to study the role of the hormones of the hypothalamo-hypophyseal-adrenocortical system (HHACS) in analgesia induced by central or systemic administration of corticoliberin-releasing hormone (CRF). Studies of the contribution of HHACS hormones were performed by blocking HHACS function by administration of hydrocortisone at a pharmacological dose one week before experiments started. Blockade of HHACS function, resulting in the inability of the system to increase hormone levels, resulted in a decrease in the analgesic effect resulting from systemic administration of CRF and completely abolished the analgesic effect after central administration of CRF. These data lead to the conclusion that there are two components involved in increasing the pain sensitivity threshold in response to administration of CRF: 1) a component dependent on HHACS hormones in central and systemic administration of CRF; 2) a component independent of HHACS hormones on systemic administration of CRF. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 2, pp. 262–270, February, 2006.     

Analgesic effect of corticotropin-releasing hormone: Involvement of the hypothalamic-pituitary-adrenocortical axis into its realization

Involvement of hypothalamic-pituitary-adrenocortical axis into the analgesic effect of corticotropin-releasing hormone after its systemic administration was studied in experiments on rats. Pharmacological blockade of the hypothalamic-pituitary-adrenocortical axis decreased the duration and degree of the analgesic effect of corticotropin-releasing hormone. This analgesic effect can be mediated via two pathways: related to hormones of the hypothalamic-pituitary-adrenocortical axis and independent of these hormones. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 2, pp. 144–146, February, 2006     

The effect of physical therapy on beta-endorphin levels

Beta-endorphin (βE) is an important reliever of pain. Various stressors and certain modalities of physiotherapy are potent inducers of the release of endogenous βE to the blood stream. Most forms of exercise also increase blood βE level, especially when exercise intensity involves reaching the anaerobic threshold and is associated with the elevation of serum lactate level. Age, gender, and mental activity during exercise also may influence βE levels. Publications on the potential stimulating effect of manual therapy and massage on βE release are controversial. Sauna, mud bath, and thermal water increase βE levels through conveying heat to the tissues. The majority of the techniques for electrical stimulation have a similar effect, which is exerted both centrally and—to a lesser extent—peripherally. However, the parameters of electrotherapy have not yet been standardised. The efficacy of analgesia and the improvement of general well-being do not necessarily correlate with βE level. Although in addition to blood, increased brain and cerebrospinal fluid βE levels are also associated with pain, the majority of studies have concerned blood βE levels. In general, various modalities of physical therapy might influence endorphin levels in the serum or in the cerebrospinal fluid—this is usually manifested by elevation with potential mitigation of pain. However, a causal relationship between the elevation of blood, cerebrospinal fluid or brain βE levels and the onset of the analgesic action cannot be demonstrated with certainty.     

Effects of μ-, δ-, and κ-opioid agonists and enkephalinase inhibitor RB101 in two inbred rat strains

Analgesic and suppressive effects of selective μ- (DAGO), δ- (DME), and κ- (DAKLI) opioid agonists are compared with those of aminopeptidase N and neutral endopeptidase RB101 in rats of WAG/G and Fischer-344 rats. Fischer-344 rats were more susceptible to suppressive effects of DAGO and analgesic effect of DME. It is concluded that in these rats peculiarities of the μ- and δ-opioid systems determine susceptibility to locomotor depression and analgesia, respectively. There is no correlation between effects of DAGO and RB101 in these strains. This implies that depressive effect of RB101 is not mediated though μ-opioid systems. In contrast, the effects of DMA on pain sensitivity in WAG/G and F-344 rats are opposite to those of RB101. This suggests that specific features in the activity of cerebral δ-OS can determine the sensitivity of RB101-induced analgesia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 5, pp. 551–554, May, 1998     

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil

Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.     

Pronociceptive actions of dynorphin via bradykinin receptors

The endogenous opioid peptide dynorphin A is distinct from other endogenous opioid peptides in having significant neuronal excitatory and neurotoxic effects that are not mediated by opioid receptors. Some of these non-opioid actions of dynorphin contribute to the development of abnormal pain resulting from a number of pathological conditions. Identifying the mechanisms and the sites of action of dynorphin is essential for understanding the pathophysiology of dynorphin and for exploring novel therapeutic targets for pain. This review will discuss the mechanisms that have been proposed and the recent finding that spinal dynorphin may be an endogenous ligand of bradykinin receptors under pathological conditions to promote pain.     

Naltrexone fails to increase pain affect in response to inflammatory pain in a novel escape/avoidance paradigm

The non-specific opioid antagonist naltrexone has traditionally been used as treatment for opioid overdose, as well as in research settings as an antagonist to examine opioid and non-opioid mediated analgesia. However, the mechanisms by which this drug operates are not well understood, and its exact effects on sensory and affective pain processes remain uncertain. Various studies have demonstrated that naltrexone behaves in a paradoxical manner, leading to analgesia, no discernable changes, or an increase in pain, depending on the circumstances of the study. This imprecise spectrum of effects leads to difficulty in interpreting results in studies where naltrexone was utilized as an antagonist. Therefore, the purpose of this experiment was to further examine whether naltrexone elicits dose-dependent effects in behavioral tests designed to quantify the sensory and affective components of pain. Naltrexone was not expected to have an effect on carrageenan-induced inflammatory pain in sensory pain measures, but a dose-dependent increase was predicted in behavior related to the affective component of pain. Eighty-eight male Sprague–Dawley rats were used to test these hypotheses by measuring Mechanical Paw Withdrawal Thresholds before and after naltrexone injection and by assessing performance in the Place Escape Avoidance Paradigm test, a novel paradigm to test pain affect, in which naltrexone had not been utilized. The results demonstrated that naltrexone failed to increase place/escape avoidance behavior as anticipated, but rather produced a slight, but non-significant, decrease in escape avoidance behavior. Further research is needed to elucidate the differential effects of naltrexone on various aspects of pain-related behavior.     

Possible mechanisms of action of nitrous oxide at the opioid receptor

The difference between the analgesic and anesthetic effects of Nitrous Oxide (N2O) is emphasized. Evidence is presented indicating that N2O analgesia is mediated by an interaction with opioid receptors. Possible mechanisms by which so small a molecule as N2O could interact with the mu opioid receptor are proposed.     

Effects of Dehydroepiandrosterone Sulfate on the Conversion of Corticosterone into 11-Dehydrocorticosterone in Stress: A Regulatory Scheme

In male rats, repeated but not single exposures to stress increased the conversion of corticosterone (CS) to 11-dehydrocorticosterone (11-DHCS), particularly on the background of administration of dehydroepiandrosterone sulfate (DHEAS). Naltrexone given 20 min before DHEAS at a dose of 0.1 mg/kg, at which it selectively blocks μ opioid receptors, prevented this effect of DHEAS, which is evidence that it is mediated by μ opioid receptors. This action of DHEAS involved endogenous ACTH and was thus mediated by central regulatory mechanisms. Our results, along with published data, lead to the first proposed scheme for the physiological regulation of the interconversion of CS and 11-DHCS in conditions of repeated stress with the involvement of DHEAS and μ opioid receptors. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 8, pp. 945–951, August, 2008.     

Acute amitriptyline treatment produces non-opioid-mediated analgesia in the formalin and bee venom tests

Tricyclic antidepressants are often effective for the management of persistent pain, and several neurochemical mechanisms have been proposed. The purpose of the present study was to examine the effect of amitriptyline (AMI) in two animal models of inflammatory pain, the formalin test and the bee venom test, and to ascertain the effect of naloxone on amitriptyline analgesia. A single dose of AMI (20 mg/kg) was found to significantly decrease both phases of formalin pain responses and the initial 10 min of bee venom pain responses. However, naloxone (3 mg/kg) had no effect on AMI analgesia in either test. The results show that single doses of AMI can decrease pain behavior in tests of tonic pain and suggest that non-opioid mechanisms may play a role in addition to opioid mechanisms demonstrated in earlier studies.     

Ontogeny of an endogenous, nonopioid and hormonally mediated analgesic system

Rats of different ages (10-day, 28-day, and 3-month-old) were exposed to cold-water stress in order to activate an endogenous analgesic system. The effects of naltrexone (7 mg/kg) and dexamethasone (.4 mg/kg) were also studied to examine the role of the opioid and hormonal systems in cold-water-induced analgesia. Following cold-water exposure, nociception was measured with the tail-flick procedure for 2 hr. Results revealed that cold water produced a significant level of analgesia in the 10-day, 28-day, and 3-month-old age groups with no differences between age groups. In addition, in each age group naltrexone did not block the analgesia while dexamethasone attenuated the analgesia produced by cold water. The effects of naltrexone and dexamethasone confirm that cold-water immersion activates a nonopioid, hormonally mediated analgesic system in each age group. Thus, this experiment found that the endogenous, nonopioid, and hormonally mediated analgesic system activated by cold water is functional early in the development of the rat. The early development of this hormonally mediated analgesic system is in contrast to the slower development of endogenous analgesia systems that are mediated by the central nervous system.     

Higher pain scores, similar opioid doses and side effects associated with antipyretic analgesics in specialised tertiary pain care

Purpose  

To evaluate whether non-opioid antipyretic analgesics are associated with lower pain scores, opioid doses and side effects in pain patients in tertiary care.