Opioid Mechanisms Research Articles

Estrogens as arbiters of sex-specific and reproductive cycle-dependent opioid analgesic mechanisms.

The organization of estrogenic signaling in the CNS is exceedingly complex. It is comprised of peripherally and centrally synthesized estrogens, and a plethora of types of estrogen receptor that can localize to both the nucleus and the plasma membrane. Moreover, CNS estrogen receptors can exist independent of aromatase (aka estrogen synthase) as well as oligomerize with it, along with a host of other membrane signaling proteins. This ability of CNS estrogen receptors to either to physically pair or exist separately enables locally produced estrogens to act on multiple spatial levels, with a high degree of gradated regulation and plasticity, signaling either in-phase or out-of phase with circulating estrogens. This complexity explains the numerous contradictory findings regarding sex-dependent pain processing and sexually dimorphic opioid antinociception. This review highlights the increasing awareness that estrogens are major endogenous arbiters of both opioid analgesic actions and the mechanisms used to achieve them. This behooves us to understand, and possibly intercede at, the points of intersection of estrogenic signaling and opioid functionality. Factors that integrate estrogenic actions at subcellular, synaptic, and CNS regional levels are likely to be prime drug targets for novel pharmacotherapies designed to modulate CNS estrogen-dependent opioid functionalities and possibly circumvent the current opioid epidemic.

Emergency Department and Hospital Care for Opioid Use Disorder: Implementation of Statewide Standards in Rhode Island, 2017-2018.

In March 2017, Rhode Island released treatment standards for care of adult patients with opioid use disorder. These standards prescribe three levels of hospital and emergency department treatment and prevention of opioid use disorder and opioid overdose and mechanisms for referral to treatment and epidemiological surveillance. By June 2018, all Rhode Island licensed acute care facilities had implemented policies meeting the standards' requirements. This policy has standardized care for opioid use disorder, enhanced opioid overdose surveillance and response, and expanded linkage to peer recovery support, naloxone, and medication for opioid use disorder.

Pain chronification and chronic pain impair a defensive behavior, but not the ability of acute pain to facilitate it, through the activation of an endogenous analgesia circuit.

The endogenous ability to decrease pain perception during life-threatening situations is crucial to the prevention of recuperative behaviors and to leave the subject free to engage in appropriated defensive responses. We have previously shown that acute pain activates the ascending nociceptive control-an endogenous analgesia circuit dependent on opioid mechanisms within nucleus accumbens-to facilitate the tonic immobility response, an innate defensive behavior. Now we asked whether chronic pain and pain chronification impairs either the tonic immobility response or the ability of acute pain to facilitate it by activating the ascending nociceptive control. We found a significant decrease in the duration of the tonic immobility response in rats during the induction and maintenance phases of the persistent mechanical hyperalgesia. This finding suggests that chronic pain and its development impair defensive responses. However, during the induction and maintenance phases of persistent hyperalgesia, the ascending nociceptive control activation, by a forepaw capsaicin injection, increased the tonic immobility response, an effect prevented by the blockade of μ-opioid receptors within nucleus accumbens. This finding suggests that pain chronification and chronic pain do not prevent the ability of acute pain to facilitate the defensive behavior of tonic immobility by activating the ascending nociceptive control. Therefore, although chronic pain states decrease the ability to engage in a defensive behavior, they may not prevent the expression of defensive behaviors during life-threatening situations accompanied by acute pain. The biological purpose of such a mechanism may be to increase the chances of survival of a wounded subject exposed to acute pain in a novel life-threatening situation. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Mansoa alliacea extract presents antinociceptive effect in a chronic inflammatory pain model in mice through opioid mechanisms

In some chronic disorders, as in arthritis, the inflammatory pain persists beyond the inflammation control becoming pathological. Its treatment shows limited efficacy and adverse effects which compromises patients' quality of life. Mansoa alliacea, known as ‘cipo alho’, is popularly used as analgesic and others species of this genus show anti-inflammatory actions. We investigated the anti-inflammatory and antinociceptive potential of M. alliacea extract in an inflammatory pain model which presents inflammatory characteristics similar to those caused by arthritis, through of the intraplantar injection of complete Freund's adjuvant (CFA) in mice. The extract chromatographic analysis revealed the presence of ρ-coumaric, ferulic and chlorogenic acids, luteolin, and apigenin. The treatment with M. alliacea prevented and reversed the CFA-induced mechanical allodynia with maximum inhibition (Imax) of 100% and 90 ± 10%, respectively. The co-administration of M. alliacea extract plus morphine enhanced the anti-allodynic effect with Imax of 100%. The M. alliacea extract also reverted the CFA-induced thermal hyperalgesia with Imax of 3.6 times greater compared to the vehicle and reduced the thermal threshold under physiological conditions. However, M. alliacea extract did not reduce the CFA-induced edema and myeloperoxidase activity. Additionally, non-selective and δ-selective opioid receptor antagonists, but not κ-opioid, prevented extract anti-allodynic effect with Imax of 98 ± 2% and 93 ± 2%, respectively. Moreover, M. alliacea extract did not induce adverse effects commonly caused by opioids and other analgesic drugs, at least in the tested pharmacological doses after the acute treatment. M. alliacea extract presents antinociceptive activity in an inflammatory pain model, which presents inflammatory characteristics similar to those arthritis-induced, without causing adverse effects in tested pharmacological doses. These effects seem to be mediated mainly via δ-opioid receptors.

Does 'Strong Analgesic' Equal 'Strong Opioid'? Tapentadol and the Concept of 'µ-Load'.

IntroductionThe distinct properties of the centrally-acting analgesic tapentadol derive from the combined contributions of an opioid component and a nonopioid component. However, the opioid component’s relative contribution to analgesic and adverse effects has not previously been elucidated. Tapentadol’s analgesic effect derives from the combined contribution of an opioid mechanism and a nonopioid mechanism, the extent of which can vary for different pains. Likewise, the interaction can vary for various adverse effects. Hence, the contribution of each mechanism to adverse effects can be different from the contribution to analgesia. We here estimate the percent contribution of each component of the mechanism of action to analgesia and to adverse effects.Areas CoveredSeveral approaches to in vitro and in vivo data to estimate the contribution of tapentadol’s opioid component to analgesia and to the two important opioid adverse effects, respiratory depression and constipation. The results are then compared with clinical data.Expert OpinionTraditional opioids, such as morphine, oxycodone, and others, produce their analgesic effects primarily through a single mechanism—the activation of µ-opioid receptors (MOR). Therefore, the contribution of the opioid component to adverse effects is 100%. In contrast, the newer strong analgesic tapentadol produces its analgesic effect via two separate and complementary analgesic mechanisms, only one of which is µ-opioid. We applied standard drug–receptor theory and novel techniques to in vitro and in vivo data to estimate by several different ways the μ-load of tapentadol (the % contribution of the opioid component to the adverse effect magnitude relative to a pure/classical µ-opioid at equianalgesia) in respiratory depression and constipation, and we compared the results to clinical evidence. The estimate is remarkably consistent over the various approaches and indicates that the μ-load of tapentadol is ≤ 40% (relative to pure MOR agonists, which have, by definition, a µ-load of 100%).FundingGrünenthal GmbH.

Opioid-Independent and Opioid-Mediated Modes of Pain Modulation.

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

Effects of isopulegol in acute nociception in mice: Possible involvement of muscarinic receptors, opioid system and l-arginine/NO/cGMP pathway

Previous studies have shown that isopulegol has anxiolytic, anticonvulsant, gastro-protective and antioxidant activities in rodents, but until now there are no studies showing activity of isopulegol in animal models of nociception and inflammation. The objective of this study was to evaluate the antinociceptive effect of isopulegol and to propose possible mechanisms involved in its effects observed in mice. Groups of male and female Swiss mice (20–35 g, n = 5–8) were used in this test under the authorization of Ethics Committee on Animal Experimentation (CEEA/UFPI N° 82/2014). In order to evaluate the antinociceptive activity of isopulegol, nociception was induced using formalin test, capsaicin and glutamate in hind paw licking model, followed by the investigation of the involvement of opioid mechanisms, K + ATP channels, muscarinic, L arginine-nitric oxide and cGMP. The oral administration of isopulegol showed antinociceptive effect in both phases of the formalin test at doses from 0.78 to 25 mg/kg (first phase) and 1.56–25 mg/kg (second phase) and also produced significant results before capsaicin test at doses from 1.56 to 12.5 mg/kg and glutamate test at doses from 3.12 to 6.25 mg/kg with a dose-dependent effect. The antinociception activity of isopulegol was inhibited in the presence of naloxone (2 mg / kg, ip), glibenclamide (3 mg/kg, ip), atropine (1 mg/kg, ip), l-arginine (600 mg/kg, ip) and methylene blue (20 mg/kg, ip). The results suggested that acute antinociceptive action of opioid isopulegol seems to be related to the K + ATP channels system, through the involvement of muscarinic receptors, inhibiting nitric oxide and cGMP.

Spinal interneuronal mechanisms underlying pudendal and tibial neuromodulation of bladder function in cats

This study examined the mechanisms underlying pudendal and tibial neuromodulation of bladder function at the single neuron level in the spinal cord. A microelectrode was inserted into the S2 spinal cord of anesthetized cats to record single neuron activity induced by bladder distention over a range of constant intravesical pressures (10–40 cmH2O). Pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) was applied at 5 Hz frequency and 0.2 ms pulse width and at multiples of the threshold (T) intensities for inducing anal or toe twitches. A total of 14 spinal neurons from 11 cats were investigated. Both PNS and TNS at 2 T intensity significantly (p < .05) reduced by 40–50% the frequency of firing induced by bladder distention at 20–40 cmH2O in the same spinal neurons. This reduction was not changed by blocking opioid receptors with naloxone (1 mg/kg, i.v.). Activation of pudendal afferents by repeatedly stroking (3–5 times per second) the genital skin using a cotton swab also inhibited the neuron activity induced by bladder distention. Prolonged (30 min) TNS at 4 T intensity produced a short lasting (10–18 min) post-stimulation inhibition that reduced by 40–50% bladder-related neuron activity at different bladder pressures. These results indicate that PNS and TNS inhibition of reflex bladder activity may be mediated in part by convergence of inhibitory inputs onto the same population of bladder-related interneurons in laminae V-VII of the S2 spinal cord and that an opioid receptor mechanism is not involved in the inhibition.

Binge-like intake of sucrose reduces the rewarding value of sucrose in adult rats.

Binge eating disorder is the most common eating disorder, but its underlying etiology is poorly understood. Both humans and animals exhibit binge-like intake of highly-palatable food, suggesting that the behavior is driven by the rewarding properties of food, rather than homeostatic signals. Food reward is regulated, in part, by endogenous opioid mechanisms which, themselves, may be altered by excessive eating. We examined this hypothesis by testing whether binge-like sucrose intake modifies the subsequent development of a conditioned place preference (CPP) to sucrose and morphine in both female and male adult rats. Separate groups were given intermittent (12h) or continuous (24 h) access to a sweet solution (10% sucrose or 0.1% saccharin) and food in their home cage over 28 days. Intermittent sucrose access induced binge-like intake, defined as increased consumption within the first hour; importantly, daily sucrose intake was similar for continuous and intermittent access groups. In a later test, all rats developed a conditioned place preference (CPP) to 15% sucrose with the exception of female and male rats given 12-h intermittent access to sucrose. In a separate experiment, all groups displayed a CPP to morphine (4 mg/kg). These findings demonstrate that binge-like sucrose intake, not just increased consumption, disrupts reward processing without affecting stimulus-reward learning. This fits with clinical evidence of hypo-reward responsivity in patients with binge eating disorder.

Assessing Opioid Tolerance Mechanisms in an Isolated Murine Dorsal Root Ganglia Neuron Model

Our current understanding of tolerance development to opioids has largely been collected through whole‐animal studies and cell culture models, yet many questions related to the underlying mechanisms remain. One approach our lab has employed is the use of isolated dorsal root ganglia (DRG) neurons from adult mice as an ex vivo native cell culture model to study the effects of opioids on neurons and to further our understanding of tolerance development within a single cell. Our initial studies focused on comparing morphine and oxycodone, two opioids widely used clinically for the treatment of pain. Interestingly, oxycodone and morphine are known to differ in antinociceptive potency and oral bioavailability when tested in whole animals, yet we found using whole‐cell patch clamp electrophysiology that acute oxycodone and morphine had similar potencies in DRG neurons. A significant decrease in neuronal excitability as measured by an increase in the potential required to fire an action potential (i.e. threshold potential) from baseline was observed following the application of 3 μM oxycodone (p &lt; 0.01) or morphine (p &lt; 0.05). Marked increases in threshold potential occurred rapidly, within five to ten minutes of drug application. When incubated in media containing 3 μM morphine, DRG neurons displayed tolerance development to a morphine challenge two days later as indicated by no change in threshold potential (p &lt; 0.05). Tolerance was observed following overnight incubation in media containing 10 μM of either morphine or oxycodone (p &lt; 0.05). β‐arrestin 2 knockout (β‐arr2 KO) mice do not develop antinociceptive tolerance to morphine in vivo, and we found that DRG neurons isolated from β‐arr2 KO mice and incubated in 10 μM morphine continued to respond to a 3 μM morphine challenge, which showed that tolerance to morphine did not develop in a single‐cell preparation (p &lt; 0.05). We further observed that overnight oxycodone incubation did not produce tolerance in β‐arr2 KO DRGs (p &lt; 0.05), providing evidence that β‐arrestin 2 plays a role in tolerance development to both oxycodone and morphine. Our lab has also shown a substantial role of protein kinase C (PKC) in morphine antinociceptive tolerance in vivo using warm water tail withdrawal studies. We tested an inhibitor of PKC, Bisindolylmaleimide XI, on DRG neurons incubated overnight with 10 μM oxycodone and found a rapid reversal of tolerance to oxycodone (p &lt; 0.01). These data indicate that PKC‐mediated mechanisms also underlie oxycodone tolerance, similarly to that of morphine tolerance, and operate at the single‐cell level. Opioid tolerance mechanisms are undoubtedly complicated and involve multiple signaling molecules, including β‐arrestin 2 and PKC. DRG neurons are a solid model bridging in vivo and in vitro studies to investigate cellular mechanisms of opioid tolerance.Support or Funding Information5T32DA007027P30DA033934This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nature's first "atypical opioids": Kratom and mitragynines.

Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are "multimechanistic") and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more-modern analgesics combine opioid and non-opioid mechanisms, and have become known as "atypical opioids." Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non-opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non-opioid properties. Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines-Nature's "atypical opioids."

3-Hydroxy-piperidinyl-N-benzyl-acyl-arylhydrazone derivatives reduce neuropathic pain and increase thermal threshold mediated by opioid system

Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a–d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6 h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.

Immediate Effects of Core Stabilization Exercise on β-Endorphin and Cortisol Levels Among Patients With Chronic Nonspecific Low Back Pain: A Randomized Crossover Design

ObjectiveThe main objective of the study was to measure the levels of plasma β-endorphin (PB) and plasma cortisol (PC) under lumbar core stabilization exercise (LCSE), placebo and control conditions in patients with chronic nonspecific low back pain. MethodsTwenty-four participants with chronic nonspecific low back pain participated in a randomized, placebo-controlled, crossover design study. There were 3 experimental exercise conditions: control condition (positioning in crook lying and rest), placebo condition (passive cycling in crook lying using automatic cycler), and LCSE on a Pilates device tested with a 48-hour interval between sessions by concealed randomization. A blood sample was collected before and after the exercise conditions. Plasma β-endorphin and PC were measured through enzyme-linked immunosorbent assay and electrochemiluminescence in a Cobas E411 auto analyzer. ResultsA significant difference in PB level was identified before and after the LCSE condition (P < .05), whereas no significant differences were noted in control and placebo exercise conditions. Also, the trend of elevation of PB under the LCSE was significantly different compared with the placebo and control conditions (P < .01). In contrast, the PC level remained unchanged in all 3 conditions. ConclusionThe findings of this study indicate that LCSE could possibly influence PB but not PC level among patients with chronic nonspecific low back pain. The mechanism of action of the pain-relieving effect of LCSE might be related to an endogenous opioid mechanism as part of its effects and might not be involved with a stress-induced analgesia mechanism.

Opioid and α2 adrenergic mechanisms are activated by GABA agonists in the lateral parabrachial nucleus to induce sodium intake

The activation of GABA, opioid or α2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or α2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or α2-adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABAA and GABAB agonists, respectively, 0.5 nmol/0.2 μl) into the LPBN induced strong ingestion of 0.3 M NaCl (45.8 ± 7.3 and 21.8 ± 4.8 ml/240 min, respectively) and water intake (22.7 ± 3.4 and 6.6 ± 2.5 ml/240 min, respectively). Naloxone (opioid antagonist, 150 nmol/0.2 μl) into the LPBN abolished 0.3 M NaCl and water intake to muscimol (2.0 ± 0.6 and 0.9 ± 0.2 ml/240 min, respectively) or baclofen (2.3 ± 1.1 and 0.8 ± 0.4 ml/240 min, respectively). RX 821002 (α2 adrenoceptor antagonist, 10 nmol/0.2 μl) into the LPBN reduced 0.3 M NaCl intake induced by the injections of muscimol or baclofen (26.6 ± 8.0 and 10.1 ± 4.9 ml/240 min, respectively). RX 821002 reduced water intake induced by muscimol (7.7 ± 2.9 ml/240 min), not by baclofen. The results suggest that sodium intake caused by gabaergic activation in the LPBN in normohydrated rats is totally dependent on the activation of opioid mechanisms and partially dependent on the activation of α2 adrenergic mechanisms in the LPBN.

Methylnaltrexone reduced body weight gain in ob/ob mice

Opioids may function to regulate food intake and body weight, an activity that could be predominantly centrally mediated. In this study, the authors evaluated the effects of a peripherally acting opioid receptor antagonist, methylnaltrexone, on weight changes in adult obese ob/ob mice. After a 12-day treatment with naloxone 0.3 mg/kg, weight was reduced from 63.7 +/- 1.1 g in the control group to 59.2 +/- 0.9 g in the naloxone group (p < 0.05). After a 12-day treatment with methylnaltrexone 3.0 mg/kg, weight increase completely ceased. The body weight was 63.9 +/- 1.0 g in the control group when compared with 55.9 +/- 1.2 g in the drug group (p < 0.01). The effect of methylnaltrexone (1.0 mg to 3.0 mg/kg) on weight changes was dose-dependent (p < 0.01). Methylnaltrexone significantly reduced daily food intake (p < 0.05), but did not affect body temperature and energy expenditure. Using HPLC analysis, no detectable naltrexone levels were found in association with methylnaltrexone administration. Whether the observed methylnaltrexone effects are primarily related to the antagonism of endorphinergic system remains to be investigated. Our results suggest that the peripheral opioid mechanism contributes to modulating food ingestion and methylnaltrexone may have clinical importance in obesity management.

Musical Agency during Physical Exercise Decreases Pain.

Objectives: When physical exercise is systematically coupled to music production, exercisers experience improvements in mood, reductions in perceived effort, and enhanced muscular efficiency. The physiology underlying these positive effects remains unknown. Here we approached the investigation of how such musical agency may stimulate the release of endogenous opioids indirectly with a pain threshold paradigm.Design: In a cross-over design we tested the opioid-hypothesis with an indirect measure, comparing the pain tolerance of 22 participants following exercise with or without musical agency.Method: Physical exercise was coupled to music by integrating weight-training machines with sensors that control music-synthesis in real time. Pain tolerance was measured as withdrawal time in a cold pressor test.Results: On average, participants tolerated cold pain for ~5 s longer following exercise sessions with musical agency. Musical agency explained 25% of the variance in cold pressor test withdrawal times after factoring out individual differences in general pain sensitivity.Conclusions: This result demonstrates a substantial pain reducing effect of musical agency in combination with physical exercise, probably due to stimulation of endogenous opioid mechanisms. This has implications for exercise endurance, both in sports and a multitude of rehabilitative therapies in which physical exercise is effective but painful.

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

BackgroundIn the past decade several studies have reported that in some brain areas, particularly, in the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. Given this evidence, in this study we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam microinjected into the rostral part of anterior cingulate cortex (ACC) in rats.MethodsMale Wistar experimental and control (saline) rats were implanted with a guide cannula in the ACC and tested for antinociception following microinjection of NSAIDs into the ACC in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.ResultsTreatment with each NSAID significantly enhanced the TF and HP latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented the analgesic effects of the three NSAIDs in both behavioral assays.ConclusionsThese findings support the concept that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

Stress and Addiction: When a Robust Stress Response Indicates Resiliency.

Stress reactivity research has traditionally focused on the idea that exaggerated responses to stress may have adverse effects on health. Accumulating evidence suggests that attenuated responses to stress and delayed recovery may also be problematic. This review focuses on the role of the stress response of the hypothalamic-pituitary-adrenocortical axis, the endogenous opioid system, and the cardiovascular system in hypertension, pain perception, and addictive behaviors. Results from multiple methods of assessment and stress paradigms conducted in our laboratory over the past two decades are integrated with research from other investigators and with existing theories. Research indicates that exaggerated biological and physiological responses to stress and attenuated pain perception are associated with hypertension and risk for cardiovascular diseases. This research complements work linking reduced stress responses with enhanced pain sensitivity and discomfort. Multiple studies have also demonstrated that an attenuated stress response is linked to exacerbation of withdrawal symptoms and relapse in nicotine addiction. Evidence indicates important moderators (i.e., sex, personality traits, and early life adversity) and hypothalamic-pituitary-adrenocortical- and endogenous opioid system-related mechanisms in the altered response to stress. I integrate these findings in a conceptual model emphasizing that robust stress responses in the context of addiction and relapse should be considered as a marker of resiliency. A blunted stress response may indicate long-term physiological dysregulation that could usher harmful consequences for cardiovascular disease, pain perception, and addictive disorders. The impact of dysregulation is influenced by multiple individual and situational factors that should be considered in evaluating the clinical significance of stress response dysregulation.

Antiallodynic Effects of Endomorphin-1 and Endomorphin-2 in the Spared Nerve Injury Model of Neuropathic Pain in Mice.

The spared nerve injury (SNI) model is a new animal model that can mimic several characteristics of clinical neuropathic pain. Opioids are recommended as treatment of neuropathic pain. Therefore, the present study was conducted to investigate the antinociceptive effects of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) given centrally and peripherally in the SNI model of neuropathic pain in mice. The SNI model was made in mice by sparing the sural nerve intact, when the other 2 of 3 terminal branches of the sciatic nerve (common peroneal and tibial nerves) were tightly ligated and cut. Von Frey monofilaments were used to measure the SNI-induced mechanical allodynia-like behavior. The antiallodynic effects of EM-1 and EM-2 were determined after central and peripheral administration in the SNI model of neuropathic pain. Also, the specific opioid receptor antagonists were used to determine the opioid mechanisms of EMs involved in neuropathic pain. Values were expressed as the mean ± standard deviation. Our results showed that the SNI mice developed prolonged mechanical allodynia-like behavior in ipsilateral paw after surgery, with the withdrawal threshold value being 0.061 ± 0.02 g after 14 days. EM-1 and EM-2 produced significant antiallodynic effects in ipsilateral paw after intracerebroventricular (i.c.v.) administration, more effective than that of morphine. The peak withdrawal thresholds of 10 nmol EM-1 and EM-2 determined at 5 minutes after injection were 0.92 ± 0.36 and 0.87 ± 0.33 g, respectively, higher than that of morphine (0.46 ± 0.20 g). Moreover, both EMs (10 nmol, i.c.v.) exerted significant antiallodynic effects in the contralateral paw, whereas no significant antinociceptive activity was seen after i.c.v. administration of morphine with equimolar dose. It was noteworthy that EM-1 and EM-2 produced antinociception through distinct μ1- and μ2-opioid receptor subtypes, and the EM-2-induced antiallodynia contained an additional component that was mediated by the release of endogenous dynorphin A, acting on κ-opioid receptor. In addition, the antiallodynic activities of peripheral administration of EM-1, EM-2, and morphine were also investigated. Intraplantar, but not subcutaneous administration of EM-1 and EM-2 also exhibited potent antinociception, establishing the peripheral and local effects. Both μ1- and μ2-opioid receptor subtypes, but not the δ- or κ-opioid receptors were involved in the peripheral antiallodynia of EMs. The present investigation demonstrated that both EM-1 and EM-2 given centrally and peripherally produced potent antiallodynic activities in SNI mice, and differential opioid mechanisms were involved.

Discovery and development of tramadol for the treatment of pain

ABSTRACTIntroduction: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain.Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed.Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its ‘mild effect’ on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics.