Postoperative Pain Management in Spanish Hospitals: A Cohort Study Using the PAIN-OUT Registry.

Pain after surgery remains a problem worldwide, although there are no published data on postoperative outcomes in Spain. We evaluated 2,922 patients on the first day after surgery in 13 tertiary care Spanish hospitals, using the PAIN-OUT questionnaire. The aims were to: assess postoperative outcomes and anesthetic/analgesic management in Orthopedics (ORT) and General Surgery (GEN) patients; explore the influence of the analgesic therapy on outcomes and opioid requirements; evaluate and compare outcomes and analgesic management according to surgical procedure. Mean worst pain and percentage of patients in severe pain were 5.6 (on a numeric rating scale of 0-10) and 39.4%, respectively, slightly lower than those reported in Western countries (range, 5.0-8.4 and 33-55%). Patients' pain assessment (83.1%) and information were high (63.3%), but participation in decision-making (4.8) was lower than in the United States (7.0) and Europe (Germany, France, Norway, and Denmark; mean, 5.9). Patients after orthopedic surgery had the worst outcomes. General anesthesia was more frequent in GEN patients, whereas regional (central and peripheral) was more frequent in ORT surgery patients. Mean opioid consumption (20.2 mg per patient per 24 hours, oral morphine equivalents), was lower than reported and decreased >50% after regional analgesia. Intravenous morphine patient-controlled analgesia was seldom used (6.2%). Acute opioid treatments were associated with worsened outcomes whereas multimodal analgesia (mainly antipyretic analgesics-nonsteroidal anti-inflammatory drugs-opioids) were associated with improved results. Epidurals in abdominal surgery (16.7%) were also associated with better outcomes. Presurgical chronic pain (>7) and/or chronic opioid consumption, were associated with worsened pain outcomes; the latter with a 50% increase in postoperative opioid requirements. Tibia/fibula and foot surgeries (ORT), and gastric, small intestine, and anterior abdominal wall procedures (GEN) were the most painful. Rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve postoperative outcomes. PERSPECTIVE: We analyzed postoperative outcomes and analgesic management in patients from tertiary care Spanish hospitals. The study serves as a point of comparison with other Western countries and shows that pain intensity outcomes and opioid consumption were slightly better in the Spanish population. Chronic pain before surgery (numeric rating scale score >7) and/or chronic opioid consumption, were associated with worsened pain outcomes, suggesting that rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve outcomes. Patients' pain participation in decision-making was inadequate and should be improved in Spanish hospitals.

Role of CRF1 receptor in post-incisional plasma extravasation and nociceptive responses in mice.

The corticotropin-releasing factor (CRF) is involved in a number of physiological functions including pain perception. The purpose of this study was to evaluate the role of CRF1 receptor in the long-lasting post-surgical changes in somatic nociceptive thresholds and in local inflammatory responses, using genetically engineered mice lacking functional CRF1 receptor. Animals underwent a plantar incision under anaesthesia with remifentanil (80µg/kg s.c.) and sevoflurane. Mechanical thresholds (von Frey) and plasma extravasation (Evan's blue) were evaluated at different time points. On postoperative day 20, mechanical thresholds had returned to baseline in CD1 mice (3.07±6.21%), while B6,129CRHtklee mice presented significant hyperalgesia, which was similar in wild-type (WT) (-29.81±8.89%) and CRF1 receptor knockout (KO) (-37.10±10.75%) mice, showing strain differences. The administration of naloxone (1mg/kg, s.c.) on postoperative day 21 produced hyperalgesia revealing surgery-induced latent pain sensitization. The extent of hyperalgesia was greater in KO versus WT mice, suggesting a role of CRF1 receptors in the upward modulation of endogenous opioid release. Furthermore, two days after surgery, plasma extravasation returned to baseline in WT mice but remained elevated in KO mice. In non-manipulated B6,129CRHtklee KO mice we observed an increase in the number of writhes (41.25±11.36) versus WT (23.80±4.71), while in the tail immersion test no differences could be detected. Our results show that CRF/CRF1 receptors seem to be a protective role in latent pain sensitization induced by surgery and in the local inflammatory response to injury.

Antihyperalgesic effects of dexketoprofen and tramadol in a model of postoperative pain in mice - effects on glial cell activation.

OBJECTIVES: To define likely targets (i.e. glia) and protocols (analgesic combinations) to improve postoperative pain outcomes and reduce chronic pain after surgery. Specifically, to assess the antihyperalgesic effects of the dexketoprofen : tramadol (DEX : TRM) combination, exploring the implication of glial activation. METHODS: In a mouse model of postincisional pain, we evaluated mechanical nociceptive thresholds (Von Frey) for 21 days postoperatively. We assessed DEX and TRM alone and combined (1 : 1 ratio) on postoperative hyperalgesia (POH, day 1) and delayed latent pain sensitisation (substantiated by a naloxone challenge; PS, day 21). The interactions were analysed using isobolograms, and concomitant changes in spinal glial cell activation were measured. KEY FINDINGS: On day 1, DEX completely blocked POH, whereas TRM induced 32% inhibition. TRM, but not DEX, partially (47%) protected against PS, at 21 days. Co-administration of DEX : TRM (1 : 1 ratio) showed additivity for antihyperalgesia. Both drugs and their combination totally inhibited surgery-induced microglia activation on day 1, but had no effect on surgery-induced astrocyte activation (1 day) or re-activation after naloxone (21 days). CONCLUSIONS: The DEX : TRM combination could have clinical advantages: a complete prevention of POH after surgery, together with a substantial (48%) inhibition of the development of PS by TRM. Microglia, but not astrocyte activation, could play a relevant role in the development of postoperative pain hypersensitivity.

Current pain education within undergraduate medical studies across Europe: Advancing the Provision of Pain Education and Learning (APPEAL) study.

OBJECTIVES: Unrelieved pain is a substantial public health concern necessitating improvements in medical education. The Advancing the Provision of Pain Education and Learning (APPEAL) study aimed to determine current levels and methods of undergraduate pain medicine education in Europe. DESIGN AND METHODS: Using a cross-sectional design, publicly available curriculum information was sought from all medical schools in 15 representative European countries in 2012-2013. Descriptive analyses were performed on: the provision of pain teaching in dedicated pain modules, other modules or within the broader curriculum; whether pain teaching was compulsory or elective; the number of hours/credits spent teaching pain; pain topics; and teaching and assessment methods. RESULTS: Curriculum elements were publicly available from 242 of 249 identified schools (97%). In 55% (133/242) of schools, pain was taught only within compulsory non-pain-specific modules. The next most common approaches were for pain teaching to be provided wholly or in part via a dedicated pain module (74/242; 31%) or via a vertical or integrated approach to teaching through the broader curriculum, rather than within any specific module (17/242; 7%). The curricula of 17/242 schools (7%) showed no evidence of any pain teaching. Dedicated pain modules were most common in France (27/31 schools; 87%). Excluding France, only 22% (47/211 schools) provided a dedicated pain module and in only 9% (18/211) was this compulsory. Overall, the median number of hours spent teaching pain was 12.0 (range 4-56.0 h; IQR: 12.0) for compulsory dedicated pain modules and 9.0 (range 1.0-60.0 h; IQR: 10.5) for other compulsory (non-pain specific) modules. Pain medicine was principally taught in classrooms and assessed by conventional examinations. There was substantial international variation throughout. CONCLUSIONS: Documented pain teaching in many European medical schools falls far short of what might be expected given the prevalence and public health burden of pain.

Almitrine fails to improve oxygenation during one-lung ventilation with sevoflurane anesthesia.

OBJECTIVE: Almitrine enhances hypoxic pulmonary vasoconstriction (HPV) and can improve hypoxemia related to one-lung ventilation (OLV). Studies using almitrine have been conducted without inhaled anesthetics because they could inhibit HPV, counteracting the effect of almitrine. This hypothesis, however, has not been confirmed. This study's aim was to evaluate whether almitrine could improve oxygenation when administered during OLV with sevoflurane anesthesia. DESIGN: A prospective, randomized, double-blind, placebo-controlled trial. SETTING: A tertiary care, university teaching hospital. PARTICIPANTS: Thirty adult patients undergoing open-chest thoracic surgery. INTERVENTIONS: Patients were assigned randomly to receive almitrine or placebo during OLV. Respiratory and hemodynamic variables were recorded continuously. Anesthesia was maintained with sevoflurane and remifentanil. Intraoperative techniques and medical teams were the same all over the study. MEASUREMENTS AND MAIN RESULTS: Respiratory and hemodynamic variables were measured during two-lung ventilation and during open-chest OLV. Two-way repeated-measures analysis of variance was used to compare the effects of almitrine and placebo. During OLV, PaO2 and shunt fraction worsened in all patients without significant differences between groups. At 30-minutes of OLV, PaO2 was 184±67 mmHg in the almitrine group and 145±56 mmHg in the placebo group, while shunt fraction were 31%±6% and 36%±13%, respectively. Mean pulmonary artery pressure was higher in the almitrine group (31±5 v 24±5 mmHg, p<0.001). CONCLUSIONS: During anesthesia with sevoflurane for open-chest OLV, almitrine failed to improve oxygenation and increased pulmonary artery pressure. The combination of sevoflurane and almitrine should, therefore, be avoided.

Can we prevent acute pain becoming chronic?

Differences between acute and chronic pain are discussed and predisposing factors for acute pain becoming chronic are listed. Some measures to prevent the transition form acute to chronic pain are described.

Glial cell activation in the spinal cord and dorsal root ganglia induced by surgery in mice.

In rodents, surgery and/or remifentanil induce postoperative pain hypersensitivity together with glial cell activation. The same stimulus also produces long-lasting adaptative changes resulting in latent pain sensitization, substantiated after naloxone administration. Glial contribution to postoperative latent sensitization is unknown. In the incisional pain model in mice, surgery was performed under sevoflurane+remifentanil anesthesia and 21 days later, 1 mg/kg of (-) or (+) naloxone was administered subcutaneously. Mechanical thresholds (Von Frey) and glial activation were repeatedly assessed from 30 min to 21 days. We used ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) to identify glial cells in the spinal cord and dorsal root ganglia by immunohistochemistry. Postoperative hypersensitivity was present up to 10 days, but the administration of (-) but not (+) naloxone at 21 days, induced again hyperalgesia. A transient microglia/macrophage and astrocyte activation was present between 30 min and 2 days postoperatively, while increased immunoreactivity in satellite glial cells lasted 21 days. At this time point, (-) naloxone, but not (+) naloxone, increased GFAP in satellite glial cells; conversely, both naloxone steroisomers similarly increased GFAP in the spinal cord. The report shows for the first time that surgery induces long-lasting morphological changes in astrocytes and satellite cells, involving opioid and toll-like receptors, that could contribute to the development of latent pain sensitization in mice.

Antinociceptive and anti-exudative synergism between dexketoprofen and tramadol in a model of inflammatory pain in mice.

Preclinical studies have demonstrated antinociceptive synergism between dexketoprofen (DEX) and tramadol (TRM) in acute animal models of nociception. The aim of the present study was to investigate the type of interaction between DEX and TRM in a chronic musculoskeletal pain model in mice, which fairly replicates the characteristics of chronic osteoarticular pain in humans. Inflammation was induced by a subplantar injection of complete Freund's adjuvant (CFA) in male CF1 mice. Nociceptive thresholds were evaluated using the hot plate, the nocifensive spontaneous behavior and the acetone tests, while plasma extravasation (PE) was assessed with Evan's blue. We used the following experimental groups: control (no inflammation), acute (1 day after CFA injection), and chronic inflammation (7 days after CFA). Dose-response curves for DEX and TRM, individually and combined in a 1 : 1 proportion based on their potency were obtained, and the doses that produced a 50% inhibition calculated. The isobolographic analysis revealed that in all groups of study (no inflammation, acute, and chronic inflammation), the combination of DEX : TRM was synergistic, for both the inhibition of nociception and the PE. The results suggest that the DEX : TRM (1 : 1) combination could be useful in the management of acute and chronic inflammatory musculoskeletal pains in humans; in addition, the synergistic interaction between the drugs observed both during acute and chronic inflammation suggests that less doses would be required of each drug to obtain effective analgesia.

A ¹8F-fluorodeoxyglucose MicroPET imaging study to assess changes in brain glucose metabolism in a rat model of surgery-induced latent pain sensitization.

BACKGROUND: Neuroplastic changes involved in latent pain sensitization after surgery are poorly defined. We assessed temporal changes in glucose brain metabolism in a postoperative rat model using positron emission tomography. We also investigated brain metabolism after naloxone administration. METHODS: Rats were given remifentanil anesthetic and underwent a plantar incision, with 1 mg/kg of (-)-naloxone subcutaneously administered on postoperative days 20 and 21. Using the von Frey test, mechanical thresholds were measured pre- and postoperatively at different time points in awake animals during F-fluorodeoxyglucose (F-FDG) uptake. Brain images were also obtained the day before mechanical testing, using a positron emission tomography R4 scanner (Concorde Microsystems, Siemens, Knoxville, TN). Differences in brain activity were assessed utilizing a statistical parametric mapping. RESULTS: Surgery induced minor changes in F-FDG uptake in the cerebellum, hippocampus, and posterior cortex, which extended to the thalamus, hypothalamus, and brainstem on days 6 and 7. Changes were still present on day 21. Maximal postoperative hypersensitivity was observed on day 2. The administration of (-)-naloxone on day 21 induced significant hypersensitivity, greatly enhancing the effect on F-FDG uptake. In sham-operated rats, naloxone induced changes limited to the striatum and the cerebellum. Nonnociceptive stimulation with von Frey filaments had no effect on F-FDG uptake. CONCLUSIONS: Surgery, remifentanil, and their combination induced long-lasting and significant metabolic changes in the pain brain matrix, with a positive correlation with hypersensitivity after naloxone. Changes in brain F-FDG precipitated by naloxone suggest that surgery under remifentanil anesthetic induces the greatest neuroplastic brain adaptations in opioid-related pathways involved in nociceptive processing and long-lasting pain sensitization.

Antinociceptive effects of morphine, fentanyl, tramadol and their combination, in morphine-tolerant mice.

The development of morphine-tolerance after chronic administration, reduces analgesic efficacy and is a significant clinical problem in some patients; may be managed clinically by increasing the doses of morphine and/or the administration of a second mu-opioid agonist. In morphine-tolerant mice, we investigated the presence of an interaction when two opioids are administered simultaneously. We determined the antinociceptive effects of morphine (M), fentanyl (FEN), and tramadol (TRM) individually and combined in a 1:1 proportion, based on their potency. Nociceptive thresholds were evaluated in CD1 mice using the hot plate test. Morphine tolerance was induced by the subcutaneous implantation of a 75mg morphine pellet, whereas control animals received a placebo pellet; the experiments were performed three days later. In both (placebo and morphine pellets), dose-response curves for M, FEN and TRM, individually and combined were obtained, and the doses that produced 50% inhibition (ED(50)) were determined. Sustained exposure to morphine induced a significant decrease in antinociceptive potency to acute M or FEN administration (tolerance), which was of a lesser magnitude after acute TRM; in these experiments the analysis of the interaction between chronic morphine and each opioid, demonstrated functional antagonism. The simultaneous administration of two opioids in morphine-tolerant mice, demonstrated antagonism for the M:FEN combination, whereas the effects of TRM combined with M or FEN, remained additive. The results suggest that during morphine-tolerance, TRM could be a useful drug to induce effective analgesia when combined with FEN or M.

Analysis of the opioid-opioid combinations according to the nociceptive stimulus in mice.

The purpose of the present study was to characterize the antinociceptive effects of tramadol, fentanyl and morphine, when two of them were systemically combined in a 1:1 potency ratio, in the hot plate, the acetic acid writhing, and the formalin tests in mice. Interaction indexes and isobolographic analysis were used to assess the type of interaction. Fentanyl was the most potent drug, followed by morphine and tramadol, with the exception in the phase I of formalin test. Synergistic interactions were obtained when tramadol was combined with fentanyl or with morphine in the writhing and formalin tests. But, in the hot plate only additive interactions were obtained. Changes were induced on the type of interaction depending on the level of effect of opioid-opioid combinations. Moreover, co-administration of fentanyl with morphine showed additivity, regardless of the type of stimulus. Standard rotarod test analysis confirmed intact motor coordination. The present findings suggest that the type of interaction between opioids is not only related to the nature of nociceptive stimulus but also to non-opioid analgesic pathways.

Increased spinal dynorphin levels and phospho-extracellular signal-regulated kinases 1 and 2 and c-Fos immunoreactivity after surgery under remifentanil anesthesia in mice.

In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the expression of c-Fos, prodynorphin (mRNA), and dynorphin in the spinal cord could participate in the molecular mechanisms underlying postoperative opioid-induced sensitization. In a mouse model of incisional pain, we evaluated thermal (Hargreaves test) and mechanical (von Frey) hyperalgesia during the first 21 postoperative days. Moreover, prodynorphin (mRNA, real-time polymerase chain reaction), dynorphin (enzymatic immunoassay), c-Fos expression, and ERK1/2 phosphorylation (both by immunohistochemistry) in the lumbar spinal cord were assessed. Surgery performed under remifentanil anesthesia induced a maximal decrease in nociceptive thresholds between 4 h and 2 days postoperatively (p < 0.001) that lasted 10 to 14 days compared with noninjured animals. In the same experimental conditions, a significant increase in prodynorphin mRNA expression (at 2 and 4 days) followed by a sustained increase of dynorphin (days 2 to 10) in the spinal cord was observed. We also identified an early expression of c-Fos immunoreactivity in the superficial laminae of the dorsal horn of the spinal cord (peak at 4 h; p < 0.001), together with a partial activation of ERK1/2 (4 h; p < 0.001). These findings suggest that activated ERK1/2 could induce c-Fos expression and trigger the transcription of prodynorphin in the spinal cord. This in turn would result in long-lasting increased levels of dynorphin that, in our model, could participate in the persistence of pain but not in the manifestation of first pain.

Deletion of the inducible nitric oxide synthase gene reduces peripheral morphine tolerance in a mouse model of chronic inflammation.

The implication of inducible nitric-oxide synthase (iNOS) on peripheral tolerance to morphine was evaluated in wild-type (WT) and iNOS knockout mice. Chronic inflammation was induced by subplantar (s.p.) injection of Complete Freund's Adjuvant (CFA), and morphine tolerance by subcutaneous implantation of a 75 mg morphine-pellet. Withdrawal was assessed after the intraperitoneal injection of 2 mg/kg naloxone. Antinociception was assessed (Randall-Selitto test) 5 min after a fixed dose of s.p. morphine (16 microg). In the absence of inflammation, s.p. morphine did not induce antinociception, while during CFA-inflammation produced 47.4 +/- 0.8 and 38.8 +/- 2.7% inhibitions respectively, in each genotype (P < 0.05). In morphine-tolerant mice with CFA-inflammation, no antinociception could be elicited in WT mice (2.4 +/- 0.3% inhibition); however, iNOS knockout mice showed significant antinociception (33.1 +/- 0.9%) (P < 0.001). Thus, iNOS gene deletion partially prevented tolerance to the peripheral effects of morphine, and significantly attenuated withdrawal-induced hyperactivity.

Comparative study of ropivacaine 0.5% and levobupivacaine 0.33% in axillary brachial plexus block.

BACKGROUND: The aim of this prospective, randomized, double-blind study was to compare the block induced by ropivacaine 0.5% with levobupivacaine 0.33% at the recommended dose range in upper limb surgery. These concentrations have provided equivalent block after epidural analgesia. We hypothesized that the block induced by both local anesthetics at clinical equipotent dose would be similar in axillary block. METHODS: Eighty-six patients received 30 mL of ropivacaine 0.5% (150 mg) or 30 mL of levobupivacaine 0.33% (99 mg) by axillary approach. Sensory and motor blocks were assessed in the 5 main nerve territories of the arm at 2, 5, 10, 15, 20, 25, and 30 mins and every 6 hrs for the first 24 hrs. We used the Student t test and chi test for comparison between groups and an analysis of survival. P < 0.05 was considered statistically significant. RESULTS: Onset of motor block was 9.0 mins (SD, 5.3 mins) for ropivacaine and 12.4 mins (SD, 7.8 mins) for levobupivacaine (P = 0.02). Time to be considered ready for surgery was similar in both groups: ropivacaine, 25.2 mins (SD, 5.1 mins); and levobupivacaine, 25.3 mins (SD, 6.4 mins) (t = -0.09, P = 0.93). Sensory block was 9.2 hrs (SD, 3.1 hrs) for ropivacaine and 11.3 hrs (SD, 4.1 hrs) for levobupivacaine (P = 0.01). CONCLUSIONS: Onset of motor block was significantly faster for ropivacaine than levobupivacaine (P = 0.02), but the time to be ready for surgery was similar with both drugs. Duration of sensory block was prolonged with levobupivacaine (P = 0.01).

Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: effect of a second surgery.

BACKGROUND: Remifentanil anesthesia enhances postoperative pain in animals and humans. The authors evaluated the impact of the dose (microg x kg(-1) x min(-1)) and duration of remifentanil infusion, and the effects of a second surgery on postoperative pain sensitization. METHODS: Mice received different doses of remifentanil over 30 or 60 min. The authors assessed thermal (Hargreaves) and mechanical hyperalgesia (von Frey) at 2, 4, 7, and 10 days. In other experiments, mice had a plantar incision during sevoflurane with or without remifentanil anesthesia that was repeated 27 days later, when nociceptive thresholds returned to baseline. Linear mixed models were used for statistical analysis. RESULTS: Remifentanil induced dose-dependent pronociceptive effects with calculated ED(50)s of 1.7 (95% confidence interval, 1.3-2.1) and 1.26 (1.0-1.6) microg x kg(-1) x min(-1) for thermal and mechanical hyperalgesia, respectively, which lasted longer with higher doses (P < 0.001). The duration of infusion did not alter the pronociceptive effects of remifentanil when administered at a constant dose of infusion. When given during surgery, high (2.66 microg x kg(-1) x min(-1)) or low (0.66 microg x kg(-1) x min(-1)) remifentanil increased the extent (P < 0.05) and duration (P < 0.01) of thermal and mechanical hyperalgesia. The latter was further enhanced after a second surgery performed in the same experimental conditions (P < 0.05). Surgery or remifentanil infusion, each one individually, induced significant mechanical hyperalgesia, which was greater when repeated (P < 0.05). CONCLUSIONS: In this model of incisional pain, remifentanil induces pronociceptive effects, which are dose dependent but unaltered by the duration of administration. A second surgery performed on the same site and experimental conditions induces greater postoperative hyperalgesia that is enhanced when remifentanil is used as an anesthetic.

The pro-nociceptive effects of remifentanil or surgical injury in mice are associated with a decrease in delta-opioid receptor mRNA levels: Prevention of the nociceptive response by on-site delivery of enkephalins.

The ultra-short-acting mu-opioid receptor (MOR) agonist remifentanil enhances postsurgical pain when used as main anesthetic in animal models and man. Although the mechanism/s involved are poorly characterized, changes in opioid receptor expression could be a relevant feature. Using a mouse model of postoperative pain, we assessed the expression of MOR and delta opioid receptors (DORs) and the efficacy of Herpes Simplex vector-mediated proenkephalin release (SHPE) preventing postoperative nociceptive sensitization induced by remifentanil or surgical incision. We determined MOR and DOR expressions in the dorsal root ganglia and the spinal cord after remifentanil or surgery in CD1 mice, using real-time PCR and Western blotting. We also assessed the effect of SHPE on nociception induced by remifentanil, surgery, and their combination (2 and 7 days after manipulation), using thermal and mechanical tests. Both remifentanil and surgery decreased DOR mRNA levels (up to days 2 and 4, respectively) in the dorsal root ganglia, but not in the spinal cord. No changes were observed in MOR mRNA, or in receptor-protein levels (Western) of either receptor. Pre-treatment with SHPE 7 days before manipulation prevented remifentanil-induced thermal hyperalgesia and mechanical allodynia and the increase in incisional pain observed when surgery was performed under remifentanil anesthesia. SHPE also prevented surgically induced allodynia but not hyperalgesia, which was blocked by the additional administration of RB101, an enkephalinase inhibitor. The study suggests that down-regulation of DOR contributes to remifentanil and surgery-induced nociception, and that postoperative pain is completely reversed by increasing enkephalin levels in the spinal cord and the periphery.

Effects of chronic inflammation and morphine tolerance on the expression of phospho-ERK 1/2 and phospho-P38 in the injured tissue.

Opioids are used in humans in the treatment of chronic osteoarticular pain, but the development of tolerance to the analgesic effects after continuous administration is still not well understood. The aim of the present study was to evaluate the expression of phospho-ERK 1/2 and phospho-p38 in mice with monoarthritis chronically exposed to morphine as a possible explanation for the development of tolerance. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA) and the tolerance by implantation of 75 mg morphine pellets. The results of the present study show that ERKs phosphorylation is unaltered by inflammation or morphine tolerance, each one individually, in the plantar tissue. In contrast, phospho-p38 is similarly decreased by inflammation or morphine tolerance. In naïve but not in tolerant animals, acute injection of morphine induces significant increase in phospho-p38 without any changes in phospho-ERK 1/2 expression. During inflammation, the acute injection of morphine induces a significant increase in the expression of ERK 1/2, but not in phospho-p38, in naïve animals. Phospho-ERK 1/2 expression was significantly decreased in the presence of inflammation plus tolerance. In contrast, no significant differences in phospho-p38 expression were observed between naïve and tolerant animals acutely injected with saline or morphine in presence of CFA inflammation. These results suggest that ERK but not p38 could be implicated in the development of morphine tolerance during peripheral inflammation. These experiments could contribute to establish the mechanisms implicated in the development of morphine tolerance in presence of inflammatory pain.