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Background Muscular pain is the main cause of disability worldwide. Myofascial pain of orofacial origin is a frequent condition, the treatment of which is not always accomplished with traditional treatment. Botulinum toxin type A (BTA) is being studied for the treatment of this type of pain with contradicting results. Thus, the objective of this study was to assess the efficacy of BTA in the therapeutic management of masticatory myofascial pain (MFP). Case Description A retrospective study of 100 patients with a diagnosis of MFP was conducted. The control group (50 patients) received conventional treatment (prescription of a muscle relaxant and craniocervical physical therapy). The BTA group (50 patients) received this same treatment and the infiltration of 100 units of BTA in the masticatory musculature. Subjective and objective pain ratings and range of mandibular movements were recorded before and after the treatment. No differences were found between groups in the baseline values. Statistically significant improvements were found in both groups compared with baseline values in all studied parameters. Moreover, BTA improved the subjective pain ratings compared with the control group. The administration of BTA added to the conventional treatment does not seem to improve objective pain ratings and functional measurements, but it improves the subjective pain ratings. Practical Implications The addition of BTA could be beneficial in the treatment of MFP in addition to conventional treatment, but further studies are needed to elucidate the mechanisms underlying this positive effect.

The addiction induced by the misuse of opioids, is not only a public health emergency but also a social and economic welfare. The main therapy is based on opioid antagonists. Oral and injectable naltrexone administration is the most widely used, presenting some inconveniences: poor patient adherence to the oral daily dosing schedule, cases of hepatitis and clinically significant liver dysfunction. This study proposes the in vitro e in vivo evaluation of anti-opioid properties of naloxone loaded-poly(lactic-co-glycolic) acid microparticles (NX-MP). In previous studies, NX-MP showed in vitro sustained naloxone release for one week at least. Our results demonstrate the in vitro efficacy of the NX-MP antagonizing for 7 days the morphine effect in SH-SY5Y cells and myenteric plexus-longitudinal muscle preparations isolated from guinea-pig ileum. The in vivo evaluation of the NX-MP was carried out in mice testing the antagonism of the antinociceptive effect of morphine. Results showed that subcutaneous administration of NX-MP blocked the morphine effect. The results of this work suggest that the subcutaneous administration of NX-MP enhances naloxone therapeutic efficacy as non-addictive medication and could be a promising alternative to naltrexone. Furthermore, the dose of NX-MP can be adapted to the patient necessities. It would be an interesting advantage to treat opioid-addiction., This research was partially funded by Universidad Complutense de Madrid Research Group (910939) and by Plan Nacional sobre Drogas, Gobierno de Espana

Plenty information exists regarding the effects of chronic stress, although few data exist on the effects of short-lasting stressors, which would mimic daily challenges. Differences in craniofacial and spinal nociception have been observed, thus those observations obtained in spinally innervated areas cannot be directly applied to the orofacial region. Although, opioids are considered amongst the most effective analgesics, their use is sometimes hampered by the constipation they induce. Thus, our aims were to study if a short-lasting stressor, forced swim stress (FSS), modifies nociception, morphine antinociception and constipation in rats. Animals were submitted to 10–20 min of FSS for three days, nociception and gastrointestinal transit were studied 24 h after the last swimming session. Nociception and morphine (0.6–5 mg/kg) antinociception were evaluated in the formalin and hypertonic saline tests in the orofacial area and limbs. Morphine-induced modifications in the GI transit were studied through radiographic techniques. Naloxone was administered, before each swimming session, to analyse the involvement of the endogenous opioid system on the effect of stress. Overall, stress did not alter nociception, although interestingly it reduced the effect of morphine in the orofacial tests and in the inflammatory phase of the formalin tests. Naloxone antagonized the effect of stress and normalized the effect of morphine. Stress did not modify the constipation induced by morphine. Opioid treatment may be less effective under a stressful situation, whilst adverse effects, such as constipation, are maintained. The prevention of stress may improve the level of opioid analgesia., This work was supported by the Ministerio de Ciencia e Innovación of Spain (MINCINN. SAF2012-40075-C02-01).

Muscular pain is the main cause of disability worldwide. Myofascial pain of orofacial origin is a frequent condition, the treatment of which is not always accomplished with traditional treatment. Botulinum toxin type A (BTA) is being studied for the treatment of this type of pain with contradicting results. Thus, the objective of this study was to assess the efficacy of BTA in the therapeutic management of masticatory myofascial pain (MFP).A retrospective study of 100 patients with a diagnosis of MFP was conducted. The control group (50 patients) received conventional treatment (prescription of a muscle relaxant and craniocervical physical therapy). The BTA group (50 patients) received this same treatment and the infiltration of 100 units of BTA in the masticatory musculature. Subjective and objective pain ratings and range of mandibular movements were recorded before and after the treatment. No differences were found between groups in the baseline values. Statistically significant improvements were found in both groups compared with baseline values in all studied parameters. Moreover, BTA improved the subjective pain ratings compared with the control group. The administration of BTA added to the conventional treatment does not seem to improve objective pain ratings and functional measurements, but it improves the subjective pain ratings.The addition of BTA could be beneficial in the treatment of MFP in addition to conventional treatment, but further studies are needed to elucidate the mechanisms underlying this positive effect.

Introduction To better understand the pathophysiology of chronic muscle pain, there are multiple animal models that mimic different acute/chronic pain conditions, such as carrageenan injection. Our previous studies demonstrated differences between muscles of different innervation in acute pain. In this study we characterized the effect of carrageenan in 2 muscles: masseter (trigeminal innervation) and gastrocnemius (spinal innervation). Methods Carrageenan (3%, 6%, and 9%) was injected into the masseter and gastrocnemius of rats. Mechanical, heat, and chemical nociceptive thresholds were measured for 14 days. Results Carrageenan did not induce mechanical allodynia or thermal hypersensitivity in either muscle. Instead, it induced a short-lasting mechanical hyperalgesia, greater in the masseter than in the gastrocnemius. Conclusion Carrageenan injected into the masseter and gastrocnemius induces a short-lasting hyperalgesia. These results could indicate a higher susceptibility of orofacial muscles to this type of insult and, consequently, a difference between trigeminal and spinal innervation. Muscle Nerve 56: 804-813, 2017.

Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). Methods: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. Key Results: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. Conclusions and inferences: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated., Ministerio de Ciencia e Innovación (SAF2012‐40075‐C02‐01).

[Background] Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5-HT3 antagonist, is clinically used to prevent chemotherapy-induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. [Methods] Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg)/vehicle and cisplatin (6 mg kg)/vehicle. Thereafter, nausea-like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. [Key Results] Cisplatin-induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. [Conclusions and Inferences] Cisplatin-induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5-HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation., Ministerio de Ciencia e Innovación (SAF2012‐40075‐C02‐01). L. Blanco had a contract by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo (PEJ15/BIO/TL‐0580).

Background: Food and diet are central issues for proper functioning of the cardiovascular (CV) system and gastrointestinal (GI) tract. We hypothesize that different types of dietary FAs affect CV parameters as well as GI motor function and visceral sensitivity. Methods: Male Wistar rats were fed with control diet (CTRL), diet supplemented with 7% soybean oil (SOY), SOY + 3.5% virgin coconut oil (COCO), and SOY + 3.5% evening primrose oil (EP) for 4 weeks. The content of insoluble fiber in CTRL was higher than in SOY, COCO, or EP. Body weight gain and food/water intake were measured. At day 28, biometric, biochemical, CV parameters, GI motor function (X-ray and colon bead expulsion test), and visceral sensitivity were evaluated. Changes in propulsive colonic activity were determined in vitro. The colon and adipose tissue were histologically studied; the number of mast cells (MCs) in the colon was calculated. Results: SOY, COCO, and EP had increased body weight gain but decreased food intake vs CTRL. Water consumption, biometric, biochemical, and CV parameters were comparable between groups. SOY increased the sensitivity to colonic distention. All groups maintained regular propulsive neurogenic contractions; EP delayed colonic motility (P, The funding was supported by the Medical University of Lodz (#50 2‐03/1‐156‐04/502‐14‐343‐17, #502‐03/1‐156‐04/502‐14‐343‐18 to PM and #503/1‐156‐04/503‐11‐001 to JF), Ministerio de Ciencia e Innovación (SAF2012‐40075‐C02‐01 to MIMF), and Ministerio de Ciencia, Innovación y Universidades (RTI2018‐101511‐B‐I00) and GEMD‐Allergan to RA . Universidad Rey Juan Carlos (Programa Propio de Fomento y Desarrollo de la Investigación, 2012) and Ministerio de Educación y Deporte (Subprograma de Movilidad, 2016: PRX17/00373) funded two research leaves to RA enjoyed at Dr Costa's laboratory (Flinders University of South Australia). L. Blanco had a contract by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo (PEJ15/BIO/TL‐0580).

Background: The antineoplastic drugs cisplatin and vincristine induce peripheral neuropathies. The sigma-1 receptor (σ1R) is expressed in areas of pain control, and its blockade with the novel selective antagonist MR-309 has shown efficacy in nociceptive and neuropathic pain models. Our goal was to test whether this compound reduces neuropathic signs provoked by these antitumoural drugs. Methods: Rats were treated with cisplatin or vincristine to induce neuropathies. The effects of acute or repeated administration of MR-309 were tested on mechanical and thermal sensitivity, electrophysiological activity of Aδ-primary afferents in the rat skin–saphenous nerve preparation, and gastrointestinal or cardiovascular functions. Results: Rats treated with antitumourals developed tactile allodynia, while those treated with vincristine also developed mechanical hyperalgesia. These in vivo modifications correlated with electrophysiological hyperactivity (increased spontaneous activity and hyperresponsiveness to innocuous and noxious mechanical stimulation). Animals treated with cisplatin showed gastrointestinal impairment and those receiving vincristine showed cardiovascular toxicity. A single dose of MR-309 strongly reduced both nociceptive behaviour and electrophysiological changes. Moreover, its concomitant administration with the antitumourals blocked the development of neuropathic symptoms, thus restoring mechanical sensitivity, improving the impairment of feeding behaviour and gastrointestinal transit in the cisplatin-treated group along with ameliorating the altered vascular reactivity recorded in rats treated with vincristine. Conclusion: σ1R antagonist, MR-309, reduces sensorial and electrophysiological neuropathic signs in rats treated with cisplatin or vincristine and, in addition, reduces gastrointestinal and cardiovascular side effects. Significance: σ1R antagonism could be an interesting and new option to palliate antitumoural neuropathies., To Ivan Álvarez Rodríguez, Carmen Merino and Guadalupe Pablo for their technical support. Ministerio de Ciencia e Innovación-MICINN (SAF2012-40075- C02- 01) and Esteve, Barcelona, Spain, for their financial support.

Background Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats. Methods Male Wistar rats were used for in vitro and in vivo studies. The effect of AM841 was tested on electrically induced twitch contractions of GI preparations (in vitro) and on GI motility measured radiographically after contrast administration (in vivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841. Key Results AM841 dose-dependently reduced in vitro contractile activity of rat GI preparations via CB1R, but not CB2R or opioid receptors. In vivo, AM841 acutely and potently reduced gastric emptying and intestinal transit in a dose-dependent and AM251-sensitive manner. The in vivo GI effects of AM841 at 0.1 mg/kg were comparable to those induced by WIN at 5 mg/kg. However, at this dose, AM841 did not induce any sign of the cannabinoid tetrad, whereas WIN induced significant central effects. Conclusions & Inferences The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.

[Background]: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB and CB antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. [Methods]: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB receptor antagonist) and AM630 (a CB receptor antagonist) were used to determine if CB and/or CB receptors are involved in vincristine-induced gastrointestinal dysmotility. [Key results]: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. [Conclusions]: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine., This work was supported by Ministerio de Ciencia e Innovación (SAF2009-12422-C02-01, SAF2012-40075-C02-01), Universidad Rey Juan Carlos—Comunidad de Madrid (URJC-CM-2006-BIO-0604) and Comunidad de Madrid (S-SAL/0261/2006; S2010/BMD-2308).

Visceral pain is a frequent cause of seeking medical attention, and it displays distinct anatomical and functional features that make it particularly difficult to manage. The endocannabinoid system (ECS) expression is frequently upregulated in painful viscera and its innervation, particularly under chronic inflammatory conditions or cancer. Pancreatitis, endometriosis, gastritis, irritable bowel syndrome, irritable bowel disease, lower tract urinary symptoms, and painful syndromes affecting the gonads may benefit from treatment with cannabinoid agonists (particularly of type 2 receptors, CB2R), or inhibitors of endocannabinoid degradation. Clinical research will definitely determine the usefulness of these new strategies to treat visceral pain.

[Background] When available, fluoroscopic recordings are a relatively cheap, non‐invasive and technically straightforward way to study gastrointestinal motility. Spatiotemporal maps have been used to characterize motility of intestinal preparations in vitro, or in anesthetized animals in vivo. Here, a new automated computer‐based method was used to construct spatiotemporal motility maps from fluoroscopic recordings obtained in conscious rats., [Methods] Conscious, non‐fasted, adult, male Wistar rats (n=8) received intragastric administration of barium contrast, and 1‐2 hours later, when several loops of the small intestine were well‐defined, a 2 minutes‐fluoroscopic recording was obtained. Spatiotemporal diameter maps (Dmaps) were automatically calculated from the recordings. Three recordings were also manually analyzed for comparison. Frequency analysis was performed in order to calculate relevant motility parameters., [Key Results] In each conscious rat, a stable recording (17‐20 seconds) was analyzed. The Dmaps manually and automatically obtained from the same recording were comparable, but the automated process was faster and provided higher resolution. Two frequencies of motor activity dominated; lower frequency contractions (15.2±0.9 cpm) had an amplitude approximately five times greater than higher frequency events (32.8±0.7 cpm)., [Conclusions and Inferences] The automated method developed here needed little investigator input, provided high‐resolution results with short computing times, and automatically compensated for breathing and other small movements, allowing recordings to be made without anesthesia. Although slow and/or infrequent events could not be detected in the short recording periods analyzed to date (17‐20 seconds), this novel system enhances the analysis of in vivo motility in conscious animals., This work was supported by Ministerio de Educación y Ciencia (SAF2012‐40075‐C02‐01), Comunidad de Madrid (S2010/BMD‐2308), and Banco de Santander funding grants for the Computer Vision and Image Processing Excellence Research Group (CVIP) and the Pain Research and Treatment Multidisciplinary Excellence Research Group (i+Dol). TIN2015‐69542‐C2‐1‐R (MINECO/FEDER)

Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint.

The treatment of pain, particularly neuropathic pain, is one of the therapeutic applications of cannabis and cannabinoids that is currently under investigation and that stimulates interest among clinicians and basic researchers. Animal pain models, including models of acute, antinociceptive, inflammatory and neuropathic pain, have demonstrated the antinociceptive efficacy of cannabinoids without causing serious alterations in animal behaviour. These data, together with the historic and current empiric use of cannabinoids, support the interest in the analysis of their effectiveness in treating neuropathic pain. The evaluation of controlled trials that focus on the effect of cannabinoids on neuropathic pain reveals that this class of drugs is able to significantly reduce pain perception. Nevertheless, this effect is generally weak and clinical relevance remains under evaluation. Moreover, there is a lack of controlled trials and, in particular, comparisons with other drugs generally used in the treatment of neuropathic pain. Despite the fact that further research is required to achieve a definitive assessment, current data obtained from basic research and from analysis of the available controlled trials indicate that cannabinoids can be accepted as a useful option in the treatment of neuropathic pain.

Opium and Hashish have been classically employed for the control of pain. The pharmacologic rationale for the use of these substances lies in the fact that they are able to modulate the endogenous opioid and cannabinoid systems respectively. Both systems, which depress the central nervous system (CNS), are capable of producing analgesia both in experimental animals and in humans by interfering with the transmission of pain signals (nociceptive) from the periphery to the superior centers of the CNS. We will review the main theories that explain the peripheral effects on both systems and its possible interest from the treatment of musculoskeletal pain standpoint.