Spontaneous Pain-Like Behaviors Are More Sensitive to Morphine and Buprenorphine Than Mechanically Evoked Behaviors in a Rat Model of Acute Postoperative Pain

Kabadi, Rajiv A.; Kouya, Francois; Cohen, Hillel W.; Banik, Ratan K.

doi:10.1213/ane.0000000000000571

Cited by 23 publications

(23 citation statements)

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“…Surgery consisted of a 20 mm longitudinal incision made through the skin and fascia of the plantar hind paw as previously described. 23 , 25 The flexor digitorum brevis muscle was then elevated, stressed, and incised longitudinally with the muscle origin and insertion remaining intact. The skin was closed with two mattress 5–0 silk sutures.…”

Section: Methodsmentioning

confidence: 99%

“…A rat model of incisional pain has been extensively characterized, which includes behavioral phenotypes, nociceptor sensitization, and pharmacologic modulation. 20 – 25 Additionally, our lab and others have reported that intra-plantar infiltration of capsaicin attenuates spontaneous pain behaviors and heat hyperalgesia. 26 , 27 This phenomenon provides a unique opportunity to identify neural transcriptomes that are specifically induced during incisional pain.…”

Section: Introductionmentioning

confidence: 95%

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Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

et al. 2020

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To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague–Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6–9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4–L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

et al. 2020

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“…Spontaneous foot lifting was used as a measure of spontaneous pain as described previously (Kabadi, Kouya, Cohen, & Banik, 2015). Animals were placed in individual Plexiglas chambers on a mesh floor above an angled mirror and habituated for 30 min to minimize exploratory behaviour during the assessment period.…”

Section: Methodsmentioning

confidence: 99%

Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats

Uhelski

McAdams

Johns

et al. 2020

European Journal of Pain

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Background Spontaneous pain after surgical incision is a significant problem for most post‐operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non‐opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post‐operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre‐operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. Methods The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30 min or 1 week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri‐incisional tissue biopsies. Results Intraplantar administration of capsaicin 30 min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2 weeks post‐incision, at a time when no recovery of epidermal innervation is observed. Conclusions Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision‐induced pain behaviours and reduced epidermal innervation around the incision site. The long‐lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. Significance Pre‐operative capsaicin infiltration attenuated spontaneous pain‐like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long‐lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre‐ or intra‐operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post‐operative pain and reduce the need for opioids during recovery.

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“…One week later, 3 doses of buprenorphine were administered, one at the beginning of the experiment, and then after 12 and 24 hours. The dose and interval of buprenorphine is midrange for what is commonly used for postoperative pain control (Kabadi, Kouya, Cohen, & Banik, 2015), and is considered to have an effective duration of action of 12 hours.…”

Section: Methodsmentioning

confidence: 99%

A non-invasive method to evaluate gastrointestinal transit behavior in rat

Bove

2015

Journal of Pharmacological and Toxicological Methods

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Introduction Many factors alter gastrointestinal transit. Animal models are useful for preclinical studies of gastrointestinal transit, but terminal methods do not allow later study, and stressful assessment methods will likely alter the transit of the animal. To overcome these factors, we developed a new method to assay rat total gastrointestinal transit. Methods Standard plastic cages with their bottoms cut off were placed on wire mesh floors. Custom apparatuses were built to contain fecal pellets as they fell through the floors. Webcams connected to a computer running a security program were placed to image the pellets at regular intervals. Custom food was obtained with and without blue pigment. After habituating to the cages and the non-pigmented food, the pigmented food was administered. The duration to the appearance of the first pigmented pellet was determined by reviewing the photographs. This duration represents the complete gastrointestinal behavior, including feeding. We compared 24-hour fecal pellet counts using images to counts by visual inspection, and also made hourly counts. After establishing baseline transit times and hourly fecal pellet discharge, rats were given buprenorphine, known to alter gastrointestinal transit. Transit times and hourly discharge were obtained again and compared to the baselines. Results The methods were successful in determining transit times. Baseline measures were consistent between three groups of 8 rats. Visual and image-based counts were highly correlated. Transit times and hourly pellet discharge were reduced by buprenorphine. Discussion The described method offers a relatively simple, inexpensive, and non-invasive means to measure rat gastrointestinal behaviour. The method has potential for any studies where altered total gastrointestinal transit is an experimental concern.

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Spontaneous Pain-Like Behaviors Are More Sensitive to Morphine and Buprenorphine Than Mechanically Evoked Behaviors in a Rat Model of Acute Postoperative Pain

Abstract: The present study demonstrates that a hindpaw plantar incision induces SFL behaviors in rats and that these behaviors have higher bioassay sensitivity to analgesic interventions with morphine and buprenorphine compared with mechanically evoked behaviors.

Cited by 23 publications

References 14 publications

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain

Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats

A non-invasive method to evaluate gastrointestinal transit behavior in rat

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