Systemic Morphine Research Articles

Intrathecal Drug Delivery System in Prepontine Cistern for Patients with Intractable Craniofacial Cancer Pain: A Multicenter Retrospective Study.

Patients with craniofacial cancer frequently suffer from severe pain. The traditional intrathecal, oral, or intravenous analgesics could only provide insufficient pain relief with many side effects. Thus, a more effective analgesia approach is required. This study aimed to investigate the safety and efficacy of placing the catheter of an intrathecal morphine pump in the prepontine cistern for the treatment of craniofacial cancer pain. We performed a retrospective study of patients with primary or metastatic craniofacial cancer pain who received the catheter placement of an intrathecal morphine pump into the prepontine cistern in eleven medical centers from September 2019 to December 2023. Friedman test and pairwise signed-rank test were used to evaluate the difference in numeric rating scale (NRS) scores, the number of breakthrough pain episodes, dose of intrathecal morphine, and dose of systemic morphine equivalents (oral, patch, intravenous) from preoperative period to postoperative days 1, 7, and 30. P values were corrected for multiple comparisons using Bonferroni test. The study included 33 patients. The median (interquartile range [IQR]) of NRS scores at days 1, 7, and 30 postimplant were 2.0 (1.0-3.5), 2.0 (1.0-2.0), and 1.0 (1.0-2.0), respectively, which was significantly lower than that before surgery (median, 8.0; IQR, 7.0-10.0; all P < .001). Compared to baseline number/d of breakthrough pain episodes (median, 6.0; IQR, 4.5-10.0), there was a progressive decrease in the number/d of breakthrough pain episodes at day 1, day 7, and day 30 postimplant, and the median (IQR) were 1.0 (0.0-3.0), 2.0 (0.0-3.0), and 0.0 (0.0-1.2), respectively (all P < .001). Approximately 78.8% and 96.7% of patients reported pain relief >50% at days 1 and 30 postimplant, respectively. Compared with that at day 1 postimplant, the proportion of patients with a pain relief rate >75% at day 30 postimplant also increased with continued intrathecal treatment. Compared to the dose of baseline systemic morphine equivalents (median, 228 mg.d-1; IQR, 120-408 mg.d-1), the dose of systemic morphine equivalents reduced significantly from 0(0-120) mg.d-1 at day 1 postimplant (P = .001), to 0 (0-0) mg.d-1 at days 7 and 30 postimplant (both P < .001). Few patients reported perioperative adverse events, including nausea, constipation, hypotension, urinary retention, dry mouth, headache, and sedation. No severe adverse events occurred. Placing the catheter tip of an intrathecal morphine pump into the prepontine cistern could effectively relieve refractory craniofacial cancer pain with an extremely low total morphine dose requirement and few adverse events. This procedure could be considered in patients with severe refractory craniofacial cancer pain.

Loss of ATP-Sensitive Potassium Channel Expression and Function in the Nervous System Decreases Opioid Sensitivity in a High-Fat Diet-Fed Mouse Model of Diet-Induced Obesity.

During diabetes progression, β-cell dysfunction due to loss of potassium channels sensitive to ATP, known as KATP channels, occurs contributing to hyperglycemia. The aim of this study is to investigate if KATP channel expression or activity in the nervous system was altered in a high-fatdiet-( HFD) fed mouse model of diet-induced obesity. Expression of two KATP channel subunits, Kcnj11 (Kir6.2) and Abcc8 (SUR1), were decreased in the peripheral and central nervous system in HFD mice, which is significantly correlated with mechanical paw withdrawal thresholds. HFD mice had decreased antinociception to systemic morphine compared to control diet (CON) mice, which was expected as KATP channels are downstream targets of opioid receptors. Mechanical hypersensitivity in HFD mice was exacerbated after systemic treatment with glyburide or nateglinide, KATP channel antagonists clinically used to control blood glucose levels. Upregulation of SUR1 and Kir6.2, through an adenovirus delivered intrathecally, increased morphine antinociception in HFD mice,. These data present a potential link between KATP channel function and neuropathy during early stages of diabetes. There is a need for increased knowledge in how diabetes affects structural and molecular changes in the nervous system, including ion channels, to lead to the progression of chronic pain and sensory issues.

Comparison of systemic morphine, nalbuphine, and epidural analgesia on acute and chronic postoperative pain in laparoscopic colorectal surgery: a randomized controlled trial

Comparison of systemic morphine, nalbuphine, and epidural analgesia on acute and chronic postoperative pain in laparoscopic colorectal surgery: a randomized controlled trial

Systemic Morphine but Not Local Administration Shows Preventive Anti-Inflammatory Effect in a Rat Model of Capsaicin-Induced Paw Edema

Peripheral opioids and analogues have demonstrated their efficacy in controlling inflammatory response and hyperalgesia. However, it is not yet clear whether the effect on edematogenic response is determined by the action at peripheral level or by systemic opioid receptors. Methods: In this study we investigated the effects of subcutaneous, intraplantar and intraperitoneal morphine injection in rats with acute capsaicin-induced hind paw inflammation. The experiment was conducted on 50 male Sprague-Dawley rats randomly divided into 5 groups of equal numerosity. Group 1 was control group; group 2 was treated with 5 mg/kg morphine by intraperitoneal injection; group 3 with 5 mg/kg morphine injected in the back subcutaneously; group 4 and group 5 were treated respectively with 0.05 mg/kg and 0.1 mg/kg morphine locally injected in the paw before induction of neurogenic edema. Neurogenic edema was induced by the administration of 50 mcg capsaicin in 50 mcl saline in the paw. The edema was measured using a calibrated plethysmometer.

Opioids for the management of dyspnea in cancer patients: a systematic review and meta-analysis.

Dyspnea is a prevalent symptom that significantly reduces quality of life of cancer patients. Palliative treatment is necessary when the symptoms do not respond to treatment for their cause. Opioids are widely used as pharmacological therapy, but evidence for individual agents is inconsistent. The purpose of this study was to evaluate the efficacy and safety of opioids for dyspnea in cancer patients. We searched the CENTRAL, MEDLINE, EMBASE, and ICHUSHI for studies using opioids for dyspnea in adult cancer patients reported by September 2019. Screening of the retrieved literature and assessment of risk of bias and outcomes were performed by two independent authors. A meta-analysis was performed on the primary endpoint, relief of dyspnea, and secondary endpoints including quality of life, somnolence as a side effect, and serious adverse events. Twelve randomized controlled trials were evaluated regarding relief of dyspnea. Somnolence and serious adverse events were evaluated in seven and four randomized controlled trials, respectively, but no randomized controlled trials were evaluable for quality of life. Overall, opioids were more effective than placebo for dyspnea (standardized mean difference -0.43, 95% confidence interval [CI] -0.75 to -0.12). Although significant difference was found between systemic morphine and placebo in the drug-specific analysis, no significant difference could be detected in the other analyses. Systemic administration of opioids is more effective than placebo in relieving dyspnea in cancer patients. Robust evidence on the efficacy and safety of opioids on dyspnea in cancer patients is lacking, and further studies are needed.

Perioperative Analgesic Modality and Effectiveness in Paediatric Patients Who Have Undergone Common Major Urology Surgery - A Two-Year Retrospective Study

Perioperative paediatric major urology surgery pain management remains challenging. These surgeries require general anaesthesia (GA) combined with either regional analgesia technique or systemic morphine infusion for optimal pain relief. We aimed to compare and evaluate the effectiveness of both analgesic techniques. This single centre retrospective descriptive study involved 88 patients, aged 3 months to 12 years old with American Society of Anaesthesiologists (ASA) I or II status, who underwent major urology surgery under GA. Group A patients received perioperative systemic morphine while Group B received regional anaesthesia blocks (continuous caudal epidural infusion, single-shot caudal blocks or single-shot erector spinae blocks). We measured requirements of perioperative rescue intravenous (IV) fentanyl, pain scores using Face, Leg, Activity, Cry, Consolability (FLACC) scale, perioperative non-opioid IV analgesia usage and associated complications. Intraoperative rescue fentanyl in both groups was comparable. Intraoperative non-opioid analgesia and postoperative rescue fentanyl requirement were significantly higher in Group A compared to Group B (p&lt;0.001). Median FLACC scores in Group A were higher than Group B (p&lt;0.001) for first 12 hours post-surgery. Commonest complications in Group A was vomiting (38.6%) and peri-catheter leak in Group B (6.81%). Regional anaesthesia technique is superior to systemic morphine in providing analgesia in the first 12 hours post paediatric major urology surgery and is devoid of opioid side effects.

Probing pain aversion in rats with the "Heat Escape Threshold" paradigm.

The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping - a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.

Intraoperative administration of systemic/epidural/intrathecal morphine on the quality of recovery following substitutional urethroplasty with buccal mucosal graft: A randomized control trial.

Substitutional urethroplasty with buccal mucosal grafting for urethral stricture is associated with significant pain, and thus inappropriate perioperative pain management could delay postoperative recovery. The objective of our research was to determine the effects of analgesia with systemic or epidural or intrathecal morphine on quality of recovery (QoR) in patients undergoing substitutional urethroplasty with buccal mucosal grafting. This prospective, double-blinded, randomized control trial was conducted over 2 years in ASA I and II patients who underwent substitutional urethroplasty with buccal mucosal graft. Patients were randomized into three groups, and Group A received systemic morphine (0.1 mg/kg), Group B received epidural morphine (3 mg), and Group C received intrathecal morphine (150 μg). The QoR between the groups were compared postoperatively using the 40-item QoR questionnaire, and the hemodynamic variations, time taken for ambulation, resumption of oral intake, and incidence of complications were also compared. Out of the recruited 93 patients, 88 patients were analyzed. The QoR score for each domain was comparable between the three groups. The total QoR score for systemic, epidural, and intrathecal morphine groups were 189 (185-191), 189 (187-191), and 185 (183-189), respectively. Additionally, the hemodynamic variations, time taken for ambulation, and resumption of oral intake were comparable between all three groups except the incidence of postoperative nausea and vomiting (PONV) and pruritis, which were higher in the intrathecal group. All three modalities, namely systemic morphine (0.1 mg/kg), epidural morphine (3 mg), and intrathecal morphine (150 μg), offer similar QoR after substitutional urethroplasty. However, the incidence of PONV and pruritis was higher with the administration of intrathecal morphine.

Ameliorative effects of varenicline and bupropion on morphine-induced conditioned place preference in rats

Background: Rewarding properties of morphine constitue the principal reasons for drug-craving behaviors which appear during morphine addiction. Varenicline and bupropion were reported to have some positive effects on addictive substances by different studies. In this study, the effects of varenicline and bupropion on morphine rewarding properties were investigated via conditioned place preference (CPP) in rats.Methods: Conditioning was performed by intraperitoneal (i.p.) administration of morphine (10 mg/kg, i.p., 1, 3, 5, and 7 days) and saline (2,4, 6, and 8 days). To evaluate the development of dependence, subcutaneous administration of varenicline (0.5, 1 and 2 mg/kg, s.c.) or bupropion (5, 10 and 20 mg/kg, i.p.) was carried out 15 minutes before the administration of morphine. To evaluate the expression of dependence, varenicline or bupropion was administered 15 minutes before the test on 9th day. To investigate the extinction of the reward effect, drugs were tested daily on days 14, 18, and 22 and evaluated for reinstatement on 23rd day.Results: Systemic morphine administration statistically significant produced CPP. Varenicline and bupropion did not reduce the development of morphine-induced CPP. In addition, varenicline and bupropion decreased expression, reinstatement and accelerated the extinction of morphine-induced CPP. Unlike varenicline, bupropion statistically significant produced CPP and altered locomotor activity.Conclusions: These data suggest that varenicline and bupropion may be useful therapeutic pharmacological agents to reduce morphine dependence. The results of our research provide preliminary evidence to highlight the importance of the effects of varenicline and bupropion on morphine dependence. In the future, it would be appropriate to conduct mechanistic studies to explain the underlying mechanisms by using different methods on the subject.

Systemic Opioid Weaning and Low Dose Intrathecal Morphine Monotherapy for Chronic Nonmalignant Pain

Low Dose Intrathecal Morphine Monotherapy (LDITM) following systemic opioid weaning has been described to be effective in the management of Chronic Nonmalignant Pain (NMP). However, broader multicenter evidence is limited. Here, we report the ongoing Embrace TDD study evaluating pain control and opioid side effects after a change from systemic opioids to LDITM in patients with NMP administered via an implanted drug delivery system.

Investigating the Role of the Locus Coeruleus in Periaqueductal Gray-mediated Antinociception

Activity in the ventrolateral periaqueductal gray (vlPAG) has been shown to be antinociceptive and is considered to be a major component in the expression of opioid drug-induced analgesia. Canonically, opioids disinhibit vlPAG activity, which modulates neuronal responses in the rostroventral medulla (RVM) and ultimately gates spinal outflow of nociceptive information via serotonergic and opioidergic mechanisms in the spinal dorsal horn. Fundamental pharmacological studies, however, indicate that spinal noradrenergic signaling is consistently implicated in opioid antinociception, suggesting that there is a gap in our knowledge of how the vlPAG may control the release of antinociceptive neuromodulators in the dorsal horn through different output regions. Although the locus coeruleus (LC) has been shown to modulate nociception, its role in and recruitment by the canonical descending circuitry is unclear. Using genetically-encoded and anatomically-targeted viral tools, immunohistochemistry, and acute pain behavior assays in conjunction with intrathecal pharmacology in mice, we show that activity in the vlPAG is necessary for the expression of systemic morphine analgesia at low doses, and that both systemic morphine-induced and PAG-driven antinociception require opioidergic and noradrenergic signaling in the spinal cord. Additionally, we find that vlPAG projection neurons send branching axons to both the RVM and LC, which may account for the LC activation we observed in both opioid-induced and PAG-driven antinociception. These findings reveal a previously underappreciated architecture of the descending pain modulatory circuitry and advance our understanding of the circuit mechanisms by which morphine produces analgesia. Grant support from NIDA R00 DA034648, Rita Allen Foundation (non-profit), Klingenstein-Simons Foundation (non-profit).

KATP Channels Function in the Peripheral and Central Nervous Systems in a Mouse Model of Type 2 Diabetes

Over 50% of individuals with type 2 diabetes eventually develop diabetic neuropathy. There is a need for increased knowledge in how diabetes affects structural and molecular changes in the nervous system, and how current diabetes interventions affect the progression of chronic pain. Loss of KATP channel activity or function could cause nerve fiber hypersensitivity and consequently increased pain sensitivity due to neuron depolarization. Diabetic neuropathy was induced in male and female C57Bl6 mice over a total of 16 weeks by feeding the animals a high-fat diet (HFD) or corresponding control diet (12330 and 12328, Research Diets Inc., New Brunswick, NJ) for over 16 weeks. Mice on the HFD for at longer than 8 weeks have significantly lower mechanical thresholds and compared to control diet mice. Decreased expression of KATP channel subunits in the spinal cord, and dorsal root ganglia were correlated with decreased mechanical paw withdrawal thresholds. Mice fed a HFD also have decreased analgesia to systemic morphine (0-20 mg/kg, s.c.), which is exacerbated after systemic treatment with glyburide or nateglinide for four weeks, (KATP channel antagonist, glyburide or nateglinide, 50 mg/kg/day, IP or vehicle, 5% DMSO + 0.5% Tween). Upregulation of KATP channels using a viral vector strategy increased paw withdrawal thresholds to systemic morphine. Diabetes affects many adults including those with prediabetes and new-onset diabetes. It is clear that novel biomarkers and pharmaceutical targets are needed in order to (1) confront the demand for new treatments that better manage and (2) identify patients that may develop diabetic neuropathy. Further investigation of KATP channel expression and function during chronic pain syndromes, including diabetic neuropathy, may help to find sufficient treatment options for patients. This work was supported through a University of Minnesota Academic Health Center Faculty Development Grant to AHK and MLG. Funding also provided by the NIH: K01 DA042902, R01 DA051876, and UL1TR002494 (AHK).

Psychological pain and opioid receptors: Reward downshift is disrupted when tested in a context signaling morphine

A sucrose downshift causes a temporary suppression of consumption accompanied by psychological pain, a negative emotion triggered by reward loss. When administered systemically before downshift sessions, opioid agonists reduce and opioid antagonists enhance such behavioral suppression. However, little is known about the effects of signals of opioid drugs on behavior during a reward downshift episode. Research showed that morphine administration can induce a direct effect (e.g., hypoalgesia) followed by a compensatory effect (e.g., hyperalgesia). Therefore, a signal for morphine could elicit either a direct or a compensatory effect. Male Wistar rats were exposed to ten 5-min sessions of access to 32% sucrose in context A, followed by three sessions of access to 4% sucrose in context B. In parallel, animals received pairings between context B and morphine (5 mg/kg, sc) occurring each day immediately after sucrose sessions (contexts were counterbalanced). Control conditions included a saline control (no morphine injected), an unpaired control (morphine injected after exposure to B) tested in A (Experiment 1), and an unpaired control tested in B (Experiment 2). In both experiments, behavioral suppression induced by the 32-to-4% sucrose downshift was attenuated when the downshift occurred in a context previously paired with morphine. These data are consistent with the hypothesis that reward downshift is accompanied by an emotion of negative valence that can be counteracted by the conditioned release of endogenous opioids triggered by signals of morphine, much like it is attenuated by systemic morphine administration. Alternative hypotheses are also discussed.

Comparison of cervical epidural morphine with intravenous morphine administration on antinociception in adult horses using thermal threshold testing

ObjectiveTo compare the antinociceptive effects of morphine administered via cervical epidural catheter to intravenously administered morphine using a thermal threshold (TT) testing model in healthy adult horses. Study designProspective, randomized, blinded experimental study. AnimalsA total of six university-owned adult horses. MethodsHorses were instrumented with a cervical (C1–C2) epidural catheter and TT testing device with probes at withers and thoracic limb coronary bands. All horses underwent three TT testing cycles including cervical epidural morphine administration (treatment EpiM; 0.1 mg kg–1), systemic morphine administration (treatment SystM; 0.1 mg kg–1) and no morphine administration (treatment Control). Baseline TT was established prior to treatments, and TT was tested at 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, 480, 600 and 720 minutes following treatment. Horses underwent a 5 day washout period between treatments and the order of treatment was randomized. Differences between treatments were analyzed with repeated measures anova. ResultsSystemic and epidural morphine administration resulted in significantly higher TT values compared with baseline and control treatment. The duration of effect was significantly longer in treatment EpiM (10–12 hours) than in treatment SystM (1.5–2.0 hours). Horses in treatment EpiM had significantly higher TT values at time points 180–600 minutes (withers) and 300–600 minutes (coronary band) than horses in treatment SystM. Conclusions and clinical relevanceCervical epidural administration of morphine provided antinociceptive effects as measured by increased TT for 10–12 hours compared with 1.5–2.0 hours for intravenously administered morphine. No complications or adverse effects were noticed following epidural placement of a C1–C2 catheter and administration of morphine. The use of a cervical epidural catheter can be considered for analgesia administration in treatment of thoracic limb and cervical pain in the horse.

Lidocaine Plus Morphine Versus Lidocaine Plus Paracetamol for Bier Block: A Double-Blind Randomized Controlled Trial

PurposeIntravenous regional anesthesia (Bier block) is widely used as an anesthetic technique for operations of short duration of the distal upper or lower extremities. We compared the efficacy of intravenous regional anesthesia with lidocaine plus paracetamol versus lidocaine plus systemic morphine for short-duration hand and forearm surgeries. DesignA double-blind randomized controlled trial with two parallel arms: lidocaine plus morphine (control) and lidocaine plus paracetamol were carried out at a University hospital. MethodsWe included men and women aged 20 to 70 years scheduled for short surgical procedures (30-60 minutes) distal to the elbow. Intravenous regional anesthesia was carried out by injecting 45 cc lidocaine 0.5% plus 300 mg paracetamol for the paracetamol group; or 45 cc lidocaine 0.5% plus 4 mg intravenous morphine for the control group. The primary outcome was postoperative pain-free period in minutes since deflation of proximal tourniquet. The secondary outcome was the highest intensity of postoperative pain on the visual analog scale within 2 hours after deflating the proximal tourniquet. FindingsThere was no significant difference between morphine and paracetamol in the duration of postoperative pain-free period (P = .078) and the mean intensity for maximum pain (P = .106). However, severe pain was significantly more frequent in the morphine group (P = .001). Paracetamol seemed to be safer than morphine as an adjuvant to lidocaine. ConclusionsWe recommend using 2 cc paracetamol (300 mg Apotel) as the adjuvant to lidocaine for intravenous regional anesthesia.

Regional Analgesia Does Not Reduce Cancer Recurrence. Case closed

Regional Analgesia Does Not Reduce Cancer Recurrence. Case closed

Contribution of G-Protein α-Subunits to Analgesia, Hyperalgesia, and Hyperalgesic Priming Induced by Subanalgesic and Analgesic Doses of Fentanyl and Morphine.

While opioids produce both analgesia and side effects by action at μ-opioid receptors (MORs), at spinal and supraspinal sites, the potency of different opioids to produce these effects varies. While it has been suggested that these differences might be because of bias for signaling via β-arrestin versus G-protein α-subunits (Gα), recent studies suggest that G-protein-biased MOR agonists still produce clinically important side effects. Since bias also exists in the role of Gα subunits, we evaluated the role of Gαi/o subunits in analgesia, hyperalgesia, and hyperalgesic priming produced by fentanyl and morphine, in male rats. We found that intrathecal treatment with oligodeoxynucleotides antisense (AS-ODN) for Gαi2, Gαi3, and Gαo markedly attenuated hyperalgesia induced by subanalgesic dose (sub-AD) fentanyl, while AS-ODN for Gαi1, as well as Gαi2 and Gαi3, but not Gαo, prevented hyperalgesia induced by sub-AD morphine. AS-ODN for Gαi1 and Gαi2 unexpectedly enhanced analgesia induced by analgesic dose (AD) fentanyl, while Gαi1 AS-ODN markedly reduced AD morphine analgesia. Hyperalgesic priming, assessed by prolongation of prostaglandin E2-induced hyperalgesia, was not produced by systemic sub-AD and AD fentanyl in Gαi3 and Gαo AS-ODN-treated rats, respectively. In contrast, none of the Gαi/o AS-ODNs tested affected priming induced by systemic sub-AD and AD morphine. We conclude that signaling by different Gαi/o subunits is necessary for the analgesia and side effects of two of the most clinically used opioid analgesics. The design of opioid analgesics that demonstrate selectivity for individual Gαi/o may produce a more limited range of side effects and enhanced analgesia.SIGNIFICANCE STATEMENT Biased μ-opioid receptor (MOR) agonists that preferentially signal through G-protein α-subunits over β-arrestins have been developed as an approach to mitigate opioid side effects. However, we recently demonstrated that biased MOR agonists also produce hyperalgesia and priming. We show that oligodeoxynucleotide antisense to different Gαi/o subunits play a role in hyperalgesia and analgesia induced by subanalgesic and analgesic dose (respectively), of fentanyl and morphine, as well as in priming. Our findings have the potential to advance our understanding of the mechanisms involved in adverse effects of opioid analgesics that could assist in the development of novel analgesics, preferentially targeting specific G-protein α-subunits.

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia.

Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises. We tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function. A genetic model of negative affect, the Wistar-Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5-3.5 mg·kg-1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1-1 mg·kg-1 systemic naloxone), quantification of plasma β-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR). Monosodium iodoacetate-treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma β-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization. Reduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain.

Equine limb cellulitis/lymphangitis resulting in distal limb ischaemia and avulsion of the hoof capsule

SummaryLimb cellulitis/lymphangitis is a well‐recognised syndrome in horses, but there are limited published reports concerning outcomes and complications. This report describes a horse with hindlimb cellulitis/lymphangitis that developed ischaemia of the distal limb resulting in necrosis of the suspensory ligament branches and avulsion of the hoof capsule. A 16‐year‐old Thoroughbred mare was referred for further investigation and treatment of a left hindlimb cellulitis/lymphangitis. The culture of a swab taken from superficial pustules on the leg yielded a moderate growth of coliform bacteria and a profuse growth of Staphylococcus aureus. Treatment included systemic antimicrobials (based on the results of culture and sensitivity), phenylbutazone, dexamethasone, morphine and paracetamol. Following some initial clinical improvement, hyperextension of the metatarsophalangeal joint was noted on Day 5 of hospitalisation. Complete avulsion of the ipsilateral hoof capsule occurred on Day 10, and the horse was immediately euthanised. A limited post‐mortem examination revealed necrosis of the suspensory ligament branches. Fibrin thrombi, interstitial haemorrhage and oedema were identified in the suspensory ligament branches and adjacent subcutaneous tissues, with thrombi in relatively large vessels. The dermal laminae were extensively necrotic, and the majority of the lamellar vasculature contained fibrin thrombi.

Spinal A3 adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats.

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A3 adenosine receptor (A3 AR) in opioid analgesic tolerance. Intrathecal administration of the A3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A3 AR expression was not affected. Collectively, our findings indicate that spinal A3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.