Postincisional Pain Research Articles

Additive antinociceptive action of intrathecal anandamide reuptake inhibitor and morphine in the management of post-incisional pain in rats

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 μg), UCM707 (75 μg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, μ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of μ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 μg) and UCM707 (75 μg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify μ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of μ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs.

Modulation of the Inflammatory Response by Pre-emptive Administration of IMT504 Reduces Postoperative Pain in Rats and has Opioid-Sparing Effects

Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This preclinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a noncoding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 and 24 hours prior to surgery) or postoperative (6 hours after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behavior analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 hours after surgery, and accelerated recovery of basal responses from 72 hours after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behavior. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1β, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 hours after incision, of interleukin-10 and interleukin-1β, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects. PerspectiveThis preclinical study introduces the noncoding non-CpG oligodeoxynucleotide IMT504 as a novel modulator of postoperative pain and underlying inflammatory events. The opioid-sparing effects observed for IMT504 appear as a key feature that could contribute, in the future, to reducing opioid-related adverse events in patients undergoing surgical intervention.

Preemptive Analgesic Effect of Intrathecal Applications of Neuroactive Steroids in a Rodent Model of Post-Surgical Pain: Evidence for the Role of T-Type Calcium Channels.

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type Ca2+ channels (T-channels) and γ-aminobutyric acid A (GABAA) receptors in the development and maintenance of post-incisional pain. We use neuroactive steroids with distinct effects on GABAA receptors and/or T-channels: Alphaxalone (combined GABAergic agent and T-channel inhibitor), ECN (T-channel inhibitor), CDNC24 (GABAergic agent), and compared them with an established analgesic, morphine (an opioid agonist without known effect on either T-channels or GABAA receptors). Adult female rats sustained the skin and muscle incision on the plantar surface of the right paw. We injected the agents of choice intrathecally either before or after the development of post-incisional pain. The pain development was monitored by studying mechanical hypersensitivity. Alphaxalone and ECN, but not morphine, are effective in alleviating mechanical hyperalgesia when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. CDNC24 on the other hand did not offer any analgesic benefit. Neuroactive steroids that inhibit T-currents—Alphaxalone and ECN—unlike morphine, are effective preemptive analgesics that may offer a promising therapeutic approach to the treatment of post-incisional pain, especially mechanical hypersensitivity.

Involvement of Interleukin-10 in Analgesia of Electroacupuncture on Incision Pain.

Objective Postincision pain often occurs after surgery and is an emergency to be treated in clinic. Electroacupuncture (EA) is a Chinese traditional treatment widely used to cure acute or chronic pain, but its mechanism is not clear. Interleukin-10 (IL-10) is a powerful anti-inflammatory cytokine that shows neuroprotective effects in inflammation and injury in the CNS. The present study attempts to reveal that IL-10 is crucial for EA analgesia on postincision pain. Methods A model of incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of IL-10 and its receptor was detected by an immunohistochemical method. C-fiber-evoked field potentials were recorded by in vivo analysis. Results The mechanical allodynia induced by paw incision was significantly inhibited by pretreatment of EA in mice. Intrathecal injection of IL-10 neutralizing antibody (2 µg/10 µL) but not intraplantar injection (10 µg/10 µL) reversed the analgesia of EA. The upregulations of IL-10 mRNA and protein were induced by EA at 6 h and 1 d after incision, respectively. Spinal long-term potentiation (LTP), a substrate for central sensitization, was also suppressed by EA with IL-10. IL-10 recombinant protein (1 µg/10 µL, i.t.) mimicked the analgesia of EA on mechanical allodynia and inhibition on the spinal LTP. Posttreatment of EA after incision also transitorily relieved the mechanical allodynia, which can be blocked by spinal IL-10 antibody. IL-10 and its receptor, IL-10RA, are predominantly expressed in the superficial spinal astrocytes. Conclusions These results suggested that pretreatment of EA effectively prevented postincision pain and IL-10 in spinal astrocytes was critical for the analgesia of EA and central sensitization.

Multiple Inhibitory Mechanisms of Lidocaine on Bradykinin Receptor Activity in Model Sensory Neurons.

Local anesthetics (LAs) are often infiltrated subcutaneously for localized perioperative numbing. In addition to blocking nerve conduction, LAs act on pathways used by a variety of pain-inducing and inflammatory mediators. We describe the effects in isolated model sensory neurons of LAs on responses to the algogenic and sensitizing peptide, bradykinin (BK). ND/7 sensory neurons were stimulated by different concentrations of BK in the presence or absence of LAs, with transient increases in intracellular calcium (Δ[Ca]in) detected fluorometrically in fields of cells. Equilibrium saturable binding of radiolabeled BK also was conducted on the same type of cells, with and without LA. Responses to low BK (5 nM) were inhibited by lidocaine at 1 mM (approximately 35% inhibition) and 10 mM (approximately 70% inhibition), whereas responses to high BK (100 nM) were unaffected by 1 mM yet inhibited (approximately 75%) by 10 mM lidocaine. Bupivacaine (1 and 2 mM) did not reduce peak Δ[Ca]in (using 5 nM BK). Lidocaine's quaternary derivative, QX-314 (10 mM), also was ineffective on peak Ca (5 nM BK). Saturation binding of BK showed that lidocaine lowered the binding capacity (Bmax) without changing the KD, consistent with noncompetitive inhibition. At subclinical concentrations, lidocaine suppresses BK's activation of model sensory neurons. This effect adds to the known analgesic mechanisms of LAs and likely contributes to the reduction of postincisional pain.

Laser acupuncture-induced analgesic effect and molecular alterations in an incision pain model: a comparison with electroacupuncture-induced effects

Low-level laser acupuncture (LLLA) produces photobiomodulation through acupuncture point and is an alternative to low-level laser therapy. Although the analgesic effect of LLLA on chronic pain has been proven, its effect on acute postincisional pain has yet to be investigated. A plantar incision (PI) model was used to mimic human postsurgical pain. Male adult rats received GaAlAs laser irradiation at the right ST36 acupoint immediately after operation and on the following 4 days. Three laser treatment groups (two red laser groups with a 30- or 15-min treatment duration and one 30-min near-infrared laser group) were compared with sham LLLA and naive groups and an electroacupuncture (EA) group (separate study). Behavioral withdrawal thresholds of both hind paws were measured before and after incision. Expression of mitogen-activated protein kinases (p-ERK and p-p38), inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF) in the spinal cord was analyzed. All three LLLA treatments attenuated post-PI tactile allodynia in the ipsilateral paw, but only the 30-min red laser treatment affected the contralateral paw and had similar efficacy to that of EA. All laser treatments barely reduced heat hyperalgesia in both hind paws. At 3 days after PI, the 30-min red laser group showed reversed increases of PI-induced p-ERK, p-p38, and iNOS but not TNF expression in the spinal cord. Repetitive LLLA treatments ameliorated PI-induced mechanical pain. The inhibition of multiple sensitization signals highlights the unique clinical role of LLLA. Thus, LLLA is an alternative to EA as an adjuvant for postoperative pain control.

The preventive effects of dexmedetomidine on endotoxin-induced exacerbated post-incisional pain in rats.

Low-grade endotoxin (lipopolysaccharide; LPS) exposure may contribute to the development of exaggerated acute postoperative pain. In the present study, we investigated the possible impact of intraoperative administration of dexmedetomidine (DEX) on LPS-induced postoperative hyperalgesia in a rat incisional pain model. The surgical and sham-surgical animals were randomly divided into saline-treated control, 5.0mg/kg LPS-treated, 10µg/kg DEX-treated, and 5.0mg/kg LPS+10µg/kg DEX-treated groups. In the surgical animals, a 1-cm-long plantar incision was made through the skin and fascia under isoflurane anesthesia. The sham-surgical rats were only anesthetized. All treatments were administered by a single intraperitoneal (i.p.) injection 60min before surgery. Acute postoperative pain was assessed using the Rat Grimace Scale (RGS) one day before surgery (baseline) and at 2h post incision. In another experiment, the involvement of the α2-adrenergic receptor was tested using atipamezole, an α2-adrenergic receptor antagonist. In the sham-surgical animals, the RGS did not increase at 2h after sham surgery compared with the corresponding baseline values in all groups. In the surgical rats, however, the postoperative RGS value of the LPS group was significantly higher than the control group, indicating LPS-induced postoperative hyperalgesia. Administration of intraoperative DEX could prevent the development of such LPS-induced exacerbated post-incisional pain. In addition, the preventive effects of intraoperative DEX were inhibited by pretreatment with atipamezole. Our findings indicate that intraoperative DEX treatment can prevent LPS-induced exacerbated post-incisional pain via the α2-adrenergic receptor signaling pathway.

Antinociceptive effects of caloric restriction on post-incisional pain in nonobese rats

Caloric restriction (CR) increases lifespan, retards physiological signs of aging, and delays a variety of diseases. Reduction of inflammatory response was proposed as one of the molecular mechanisms for how CR exerts beneficial effects. The present study investigated the effects of CR on postoperative pain in rats. Adult nonobese rats were divided into two dietary groups, an ad libitum fed group (AL) and a caloric restriction group (CR) that was provided with 60% of the food intake of AL rats. After 6 weeks, the effects of CR on pain behaviors and inflammation induced by plantar incision were examined. CR rats displayed significantly reduced nonevoked pain, mechanical allodynia and thermal hyperalgesia induced by incision, and showed decreased levels of pro-inflammatory cytokines in serum, peri-incisional skin tissue and ipsilateral spinal cord dorsal horn at 6 h and 24 h after incision. The analgesic efficiency of parecoxib and morphine, two agents widely used for the management of postoperative pain clinically, was reinforced by CR. Together, CR generates antinociceptive effects on postoperative incisional pain in rats, perhaps providing some improvement of QOL in patients with postoperative pain, and the beneficial effects may be attributable to the inhibition of excessive inflammation induced by surgical injury.

100-Hz Electroacupuncture but not 2-Hz Electroacupuncture is Preemptive Against Postincision Pain in Rats

Preemptive analgesia involves introducing an analgesic before noxious stimulation. Electroacupuncture (EA) activates descending mechanisms that modulate nociceptive inputs into the spinal dorsal horn. This study evaluated whether preoperative EA is more effective than postoperative EA in reducing incision pain in rats. The nociceptive threshold to mechanical stimulation was utilized to examine the effects of an intraperitoneal injection of saline (0.1 mL/kg) or naloxone (1 mg/kg) on antinociception induced by a 20-minute period of 2-Hz or 100-Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints before surgical incision, or 10 minutes after or 100 minutes after surgical incision of the hind paw. The extent of mechanical hyperalgesia after the incision was significantly attenuated by the application of 100-Hz EA preoperatively, but not by its application at 10 minutes or 100 minutes postoperatively. By contrast, 2-Hz EA was effective against postoperative hyperalgesia when applied 10 minutes or 100 minutes after surgery but not when it was applied preoperatively. Only the effect of 2-Hz EA applied 10 minutes after surgery was sensitive to naloxone. The present study showed for the first time that 100-Hz EA, but not 2-Hz EA, exerts a nonopioidergic preemptive effect against postincision pain in rats.

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

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. 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. 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). 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.

Effects and underlying mechanisms of endotoxemia on post-incisional pain in rats

AimsThe aim of the present study was to investigate the effects and underlying mechanisms of endotoxin (lipopolysaccharide, LPS) on postoperative pain using a rat model of incisional pain. Main methodsAnimals were assigned to one of four groups using a 2×2 experimental design: a single intraperitoneal injection of 5mg/kg LPS versus vehicle, by plantar incision versus anesthesia alone. Spontaneous pain and mechanical paw withdrawal threshold (PWT) were evaluated using Rat Grimace Scale (RGS) and von Frey fibers, respectively. Analgesic effects of ketoprofen, morphine, and wound infiltration with ropivacaine, as well as the contribution of the Toll-like receptor (TLR) 4 pathway, were also evaluated. In vivo single fiber recordings were performed to assess the nociceptive afferent signals from the surgical site. Key findingsSystemic administration of LPS significantly increased the pain intensity at 2h after hind paw incision, but did not affect the PWT. The duration of post-incisional pain assessed by both scales did not significantly differ in the presence or absence of LPS. The analgesic efficiency of ketoprofen and morphine was reduced by LPS, while that of wound infiltration with ropivacaine was preserved. On the other hand, in vivo single fiber recording failed to demonstrate any significant effects of LPS on the activity of primary afferents due to mechanical stimuli. Pre-treatment with intrathecal LPS from Rhodobacter sphaeroides, a TLR-4 antagonist, almost completely inhibited LPS-induced exacerbated post-incisional pain, and decreased analgesic responsiveness. SignificanceThe present results suggested that LPS exacerbates post-incisional pain via the central TLR-4 pathway.

Postincisional Pain in Spinal Cord Stimulation: Incidence and Treatment

The post incisional pain is a biological complication of the spinal cord stimulation implantation. The frequency of this condition in literature reported studies ranges from 0.9% to 12%. The causes of this pain are unclear and there is no homogeneity in the reported data. The treatment of this surgical complication is not well established with several therapy proposed. Starting from our experience we stress the need for more consistent data on the frequency and on the therapies to be used.

Resolution of Inflammation by Resolvin D1 Is Essential for Peroxisome Proliferator-activated Receptor-γ-mediated Analgesia during Postincisional Pain Development in Type 2 Diabetes.

The wound healing process following acute inflammation after surgery is impaired in diabetes. Altered macrophage functions are linked to delayed tissue repair and pain development in diabetes. Although peroxisome proliferator-activated receptor (PPAR)-γ agonists are used to treat diabetes, their postoperative analgesic effects in diabetes have not been evaluated. The PPARγ agonist rosiglitazone (rosi) was injected at the incision site of diabetic (db/db) mice with resolvin (Rv) D1, a lipid mediator involved in resolution of inflammation. Pain-related behavior, neutrophil infiltration, phagocytosis, and macrophage polarity were assessed for 7 days postoperatively. Rosiglitazone and RvD1 alleviated mechanical hyperalgesia in db/db (db) mice, whereas rosiglitazone alone did not alter mechanical thresholds on days 4 (db rosi + RvD1 vs. db rosi: 0.506 ± 0.106 vs. 0.068 ± 0.12) and 7 (0.529 ± 0.184 vs. 0.153 ± 0.183) after incision (n = 10 per group). In control m/m mice, the rosiglitazone-induced analgesic effects were reversed by knockdown with arachidonate 5-lipoxygenase small interfering RNA, but these were restored by addition of RvD1. In db/db mice treated with rosiglitazone and RvD1, local infiltration of neutrophils was markedly reduced, with an associated decrease in total TdT-mediated dUTP nick-end labeling cells. Acceleration of rosiglitazone-induced phenotype conversion of infiltrated macrophages from M1 to M2 was impaired in db/db mice, but it was effectively restored by RvD1 in db/db wounds. In diabetes, exogenous administration of RvD1 is essential for PPARγ-mediated analgesia during development of postincisional pain. Resolution of inflammation accelerated by RvD1 might promote PPARγ-mediated macrophage polarization to the M2 phenotype.

Persistent pain alters AMPA receptor subunit levels in the nucleus accumbens.

BackgroundA variety of pain conditions have been found to be associated with depressed mood in clinical studies. Depression-like behaviors have also been described in animal models of persistent or chronic pain. In rodent chronic neuropathic pain models, elevated levels of GluA1 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the nucleus accumbens (NAc) have been found to inhibit depressive symptoms. However, the effect of reversible post-surgical pain or inflammatory pain on affective behaviors such as depression has not been well characterized in animal models. Neither is it known what time frame is required to elicit AMPA receptor subunit changes in the NAc in various pain conditions.ResultsIn this study, we compared behavioral and biochemical changes in three pain models: the paw incision (PI) model for post-incisional pain, the Complete Freund’s Adjuvant (CFA) model for persistent but reversible inflammatory pain, and the spared nerve injury (SNI) model for chronic postoperative neuropathic pain. In all three models, rats developed depressive symptoms that were concurrent with the presentation of sensory allodynia. GluA1 levels at the synapses of the NAc, however, differed in these three models. The level of GluA1 subunits of AMPA-type receptors at NAc synapses was not altered in the PI model. GluA1 levels were elevated in the CFA model after a period (7 d) of persistent pain, leading to the formation of GluA2-lacking AMPA receptors. As pain symptoms began to resolve, however, GluA1 levels returned to baseline. Meanwhile, in the SNI model, in which pain persisted beyond 14 days, GluA1 levels began to rise after pain became persistent and remained elevated. In addition, we found that blocking GluA2-lacking AMPA receptors in the NAc further decreased the depressive symptoms only in persistent pain models.ConclusionOur study shows that while both short-term and persistent pain can trigger depression-like behaviors, GluA1 upregulation in the NAc likely represents a unique adaptive response to minimize depressive symptoms in persistent pain states.

Role of Somatostatin and Somatostatin Receptor type 2 in Postincisional Nociception in Rats

Somatostatin (SST) and the somatostatin receptor type 2 (sstr2) are expressed in the superficial part (Laminae I–III) of the dorsal horn of the spinal cord. Since the neurons in these laminae also receive nociceptive sensation from the periphery, it was hypothesized that both SST and sstr2 could be involved in the modulation of nociceptive transmission. To the best of knowledge, there are no studies on the involvement of SST and sstr2 in hind paw incision model in rats, which mimics postoperative pain in humans. Sprague-Dawley rats were subjected to hind paw incision under isoflurane anaesthesia and the resulting mechanical allodynia and thermal hyperalgesia were evaluated for 5 days. In another set of animals, the spinal cord was isolated at specified time intervals after incision and examined for SST and sstr2 expression using immunohistochemistry and immunoblotting procedures. Finally, nociceptive parameters were again evaluated in incised rats, which had received SST (400 µg/kg i.p. three times per day). Blood glucose level and locomotor activity were determined after SST treatment. Both allodynia and hyperalgesia were highest immediately after incision. Spinal SST expression increased at 2 h. A further increase was noted on day 3. Expression of sstr2 increased initially but decreased at day 1. These changes could be due to exocytosis of SST and internalization of the ligand–receptor complex. SST injection significantly attenuated mechanical allodynia but not thermal hyperalgesia. Significant change in blood glucose level or locomotor activity was absent. SST appears to contribute to postincisional pain. This finding could be of clinical relevance.

Forced Treadmill Running Suppresses Postincisional Pain and Inhibits Upregulation of Substance P and Cytokines in Rat Dorsal Root Ganglion

Exercise causes a variety of psychophysical effects (eg, alterations in pain sensation). Tissue injury induces mediator releases in the spinal cord resulting in pain hypersensitivity; however, the contribution of the dorsal root ganglion (DRG) is poorly understood. In this study, we tested if forced treadmill running can attenuate postoperative pain and alter substance P (SP) or proinflammatory cytokine level in the DRG by using a rat model of skin/muscle incision and retraction (SMIR). We evaluated mechanical sensitivity to von Frey stimuli (6 and 15 g) and expression of SP, interleukin-1β, and interleukin-6 in the DRG of sham-operated sedentary rats, SMIR sedentary rats, sham-operated rats with forced treadmill running, and SMIR rats with forced treadmill running. At postoperative day 8, trained rats ran for 5 days per week for 4 weeks on a treadmill 70 minutes/d with an intensity of 18 m/min. On postoperative day 6, SMIR sedentary rats displayed a significant mechanical hypersensitivity that persisted until postoperative day 35. By comparison, SMIR-operated rats, which received forced treadmill running, exhibited a quick recovery from mechanical hypersensitivity. SMIR sedentary rats showed an upregulation of SP, interleukin-1β, and interleukin-6 in the DRG at postoperative days 14 and 28, whereas SMIR-operated rats receiving forced treadmill running reversed this upregulation at postoperative day 28. We concluded that forced treadmill running alleviated persistent postincisional pain caused by SMIR surgery. This appears to be protective against postoperative pain, which probably relates to the downturn in excess SP, interleukin-1β, and interleukin-6 in the DRG. PerspectiveControlling the expression of SP, interleukin-6, and interleukin-1β in the DRG can help manage postoperative pain. This finding could potentially help clinicians and physical therapists who seek to examine how exercise may attenuate postsurgical pain and its mechanism.

Locally Mediated Analgesic Effect of Bradykinin Type 2 Receptor Antagonist HOE 140 During Acute Inflammatory Pain in Rats

Opioids like morphine form the mainstay of treatment for moderate to severe burn pain. However, lack of dedicated burn care service and potentially serious side effects of opioids often compromise effective treatment. Newer drugs as well as newer routes of administration of analgesic drugs are long-felt needs in the management of burn pain. Bradykinin is a potent inflammatory mediator present at sites of tissue damage. The present study investigated the analgesic effect of bradykinin type 2 receptor antagonist HOE 140 after direct intrawound administration in rats. Also, whether the analgesic effect was locally mediated was further evaluated. Tissue damage was produced by a surgical incision involving skin, fascia, and muscle. It has been reported that there are minor differences in inflammatory mediators underlying incision-related and burn injury-related pain. HOE 140 (1, 3, or 10 μg/10 μl physiological saline) was administered into the wound by a sterile micropipette. After an interval of 30 seconds, the wound was closed. HOE 140-induced analgesic effect was compared to other experimental groups of rats which did not receive any drug or those which were treated with either saline (vehicle) or water. Postincisional pain was determined by monitoring behavior, allodynia, and thermal hyperalgesia. Analgesic effect was also determined after drug administration in contralateral paw. HOE 140 (1, 3, 10 μg) significantly relieved mechanical allodynia and guarding in comparison with vehicle-treated group. The analgesic effect of HOE 140 was locally mediated. Healing of the wound was normal. In conclusion, the results suggest that bradykinin type 2 receptor antagonists such as HOE 140 could be useful in the treatment of acute inflammatory pain.

Peripheral administration of morphine attenuates postincisional pain by regulating macrophage polarization through COX-2-dependent pathway.

BackgroundMacrophage infiltration to inflammatory sites promotes wound repair and may be involved in pain hypersensitivity after surgical incision. We recently reported that the development of hyperalgesia during chronic inflammation is regulated by macrophage polarity, often referred to as proinflammatory (M1) or anti-inflammatory (M2) macrophages. Although opioids such as morphine are known to alter the inflammatory milieu of incisional wounds through interactions with immunocytes, the macrophage-mediated effects of morphine on the development of postincisional pain have not been well investigated. In this study, we examined how morphine alters pain hypersensitivity through phenotypic shifts in local macrophages during the course of incision-induced inflammation.ResultsLocal administration of morphine in the early phase, but not in the late phase alleviated mechanical hyperalgesia, and this effect was reversed by clodronate-induced peripheral depletion of local macrophages. At the morphine-injected incisional sites, the number of pro-inflammatory F4/80+iNOS+M1 macrophages was decreased during the course of pain development whereas increased infiltration of wound healing F4/80+CD206+M2 macrophages was observed during the early phase. Morphine increased the gene expression of endogenous opioid, proenkephalin, and decreased the pronociceptive cytokine, interleukin-1β. Heme oxygenase (HO)-1 promotes the differentiation of macrophages to the M2 phenotype. An inhibitor of HO-1, tin protoporphyrin reversed morphine-induced analgesic effects and the changes in macrophage phenotype. However, local expression levels of HO-1 were not altered by morphine. Conversely, cyclooxygenase (COX)-2, primarily produced from peripheral macrophages in acute inflammation states, was up-regulated in the early phase at morphine-injected sites. In addition, the analgesic effects and a phenotype switching of infiltrated macrophages by morphine was reversed by local administration of a COX inhibitor, indomethacin.ConclusionsLocal administration of morphine alleviated the development of postincisional pain, possibly by altering macrophage polarity at the incisional sites. A morphine-induced shift in macrophage phenotype may be mediated by a COX-2-dependent mechanism. Therefore, μ-opioid receptor signaling in macrophages may be a potential therapeutic target during the early phase of postincisional pain development.

High-frequency transcutaneous electrical nerve stimulation attenuates postsurgical pain and inhibits excess substance P in rat dorsal root ganglion.

Transcutaneous electrical nerve stimulation (TENS) is a common therapeutic modality for pain management, but its effectiveness in skin/muscle incision and retraction (SMIR)-evoked pain is unknown. We aimed to examine the effects of TENS on postoperative pain and the levels of substance P (SP), N-methyl-D-aspartate receptor 1 (NR1), and interleukin 1β (IL-1β) in rat dorsal root ganglion (DRG). High-frequency (100 Hz) TENS was administered daily beginning on postoperative day 1 (POD1) and continued until animal subjects were killed for tissues. Mechanical sensitivity to von Frey stimuli (6g and 15g) and the levels of NR1, SP, and IL-1β in DRG were assessed in the sham-operated, SMIR-operated, TENS after SMIR surgery, and placebo-TENS after SMIR surgery groups. Skin/muscle incision and retraction rats exhibited a significant hypersensitivity to von Frey stimuli on POD3. In contrast with SMIR rats, SMIR-operated rats receiving TENS therapy demonstrated a rapid recovery of mechanical hypersensitivity. The SMIR-operated rats showed an up-regulation of NR1, SP, and IL-1β in DRG on PODs 14 and 28, whereas the SMIR-operated rats after TENS administration reversed this up-regulation. By contrast, the placebo-TENS after SMIR operation did not alter postsurgical pain nor the levels of NR1, SP, and IL-1β. Our data demonstrated that TENS intervention reduced persistent postoperative pain caused by SMIR operation. Up-regulation of NR1, SP, and IL-1β in DRG, activated after SMIR surgery, is important in the development of prolonged postincisional pain. The TENS pain relief may be related to the suppression of NR1, SP, and IL-1β in DRG of SMIR rats.

Comparison of electroacupuncture and morphine-mediated analgesic patterns in a plantar incision-induced pain model.

Electroacupuncture (EA) is a complementary therapy to improve morphine analgesia for postoperative pain, but underlying mechanism is not well-known. Herein, we investigated EA-induced analgesic effect in a plantar incision (PI) model in male Sprague-Dawley rats. PI was performed at the left hind paw. EA of 4 Hz and high intensity or sham needling was conducted at right ST36 prior to PI and repeated for another 2 days. Behavioral responses to mechanical and thermal stimuli, spinal phospho-ERK, and Fos expression were all analyzed. In additional groups, naloxone and morphine were administered to elucidate involvement of opioid receptors and for comparison with EA. EA pretreatment significantly reduced post-PI tactile allodynia for over 1 day; repeated treatments maintained analgesic effect. Intraperitoneal naloxone could reverse EA analgesia. Low-dose subcutaneous morphine (1 mg/kg) had stronger inhibitory effect on PI-induced allodynia than EA for 1 h. However, analgesic tolerance appeared after repeated morphine injections. Both EA and morphine could equally inhibit PI-induced p-ERK and Fos inductions. We conclude that though EA and morphine attenuate postincision pain through opioid receptor activations, daily EA treatments result in analgesic accumulation whereas daily morphine injections develop analgesic tolerance. Discrepant pathways and mechanisms underlying two analgesic means may account for the results.