Screening the Role of Pronociceptive Molecules in a Rodent Model of Endometriosis Pain

Alvarez P, Pedro Alvarez, Pedro Álvarez, Jon D. Levine
The journal of pain · 2014 · vol. 15(7) , pp. 726–733 · doi:10.1016/j.jpain.2014.04.002 · PMID:24755283 · PMC4119016 · W2143891701
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This study assessed the roles of IL-6, TNFα, and NGF in endometriosis pain by intrathecally administering antisense oligonucleotides against their receptors in a rat endometriosis model.

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This study investigated whether pronociceptive mediators IL-6, TNFα, and NGF directly drive mechanical hyperalgesia in a surgical rat model of endometriosis pain by selectively knocking down their receptors in nociceptors using intrathecal antisense oligodeoxynucleotides against gp130 (IL-6 signaling complex), TNFR1, and TrkA (NGF receptor). In adult female Sprague–Dawley rats, ectopic uterine tissue implanted onto the gastrocnemius muscle produced long-lasting mechanical hyperalgesia, and daily intrathecal receptor knockdown was performed for three days with mismatch ODN controls, with effects assessed by changes in mechanical nociceptive thresholds. The paper’s key premise is to move beyond correlational candidate mediator evidence by testing their contribution side-by-side while addressing whether they act via nociceptor activation, with the limitation that the model targets mechanical hyperalgesia measured at a specific site rather than other pain dimensions. This paper is centrally about endometriosis—specifically screening the role of IL-6, TNFα, and NGF signaling through nociceptor receptors in endometriosis pain in a rodent model.

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Abstract

UnlabelledChronic pain is a major symptom in patients with endometriosis, a common gynecologic condition affecting women in their reproductive years. Although many proalgesic substances are produced by endometriosis lesions, experimental evidence supporting their relative roles is still lacking. Furthermore, it is unclear whether these proalgesic agents directly activate nociceptors to induce endometriosis pain. To determine their relative contribution to pain associated with endometriosis, we evaluated the intrathecal administration of oligodeoxynucleotides (ODNs) antisense to messenger RNA for receptors for 3 pronociceptive mediators known to be produced by the ectopic endometrium. Two weeks after the implant of autologous uterine tissue onto the gastrocnemius muscle, local mechanical hyperalgesia was observed in operated rats. Intrathecal antisense ODN targeting messenger RNA for the interleukin 6 receptor-signaling complex subunit glycoprotein 130 and the nerve growth factor tyrosine kinase receptor A, but not their mismatch ODNs, reversibly attenuated mechanical hyperalgesia at the implant site. In contrast, intrathecal antisense ODN targeting the tumor necrosis factor receptor 1, at a dose that markedly inhibited intramuscularly injected tumor necrosis factor alpha, had only a small antihyperalgesic effect in this model. These results indicate the relative contribution of pronociceptive mediators produced by ectopic endometrial tissue to endometriosis pain. The experimental approach presented here provides a novel method to evaluate for the differential contribution of mediators produced by other painful lesions as well as endometriosis lesions as targets for novel treatment of pain syndromes.PerspectiveThis article presents evidence for the relative contribution of proalgesic mediators to primary hyperalgesia displayed by rats submitted to a model of endometriosis pain. This approach can be used to identify potential targets for the treatment of endometriosis pain.
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Intro

Endometriosis is a common and very disabling clinical condition affecting women in their reproductive years which is characterized by the presence of endometrial tissue and glands outside of the uterine cavity 24 . Chronic pelvic pain is the main symptom reported by women with endometriosis, typically evoked by mechanical stimuli, (e.g., dysmenorrhea, dyschezia, dysuria and dyspareunia) 24 , 54 . This pain is often resistant to available analgesic treatments, presumably because they are not directed to specific mediators that induce endometriosis pain. Given the complex pathophysiology of endometriosis, several mediators appear as possible candidates underlying endometriosis pain 24 . While many attempts have been made to unveil the role of these pro-algesic mediators in endometriosis pain, the available studies are correlative, direct evidence for the involvement of candidate mediators as well as side-by-side comparison of their contribution is still lacking. Furthermore, it is unclear whether these pro-nociceptive mediators directly activate nociceptors innervating endometriosis lesions or act indirectly on other cell types to induce endometriosis pain. For instance, pro-inflammatory cytokines such as tumor necrosis alpha (TNFα), interleukin 6 (IL-6) and monocyte chemoattractant protein 1 have been observed in plasma and peritoneal fluid of patients suffering endometriosis pain 42 , 50 , 56 and all of them also induce primary mechanical hyperalgesia after local injection 12 , 18 , 19 , 47 . Neurotrophins such as nerve growth factor (NGF) are also produced in endometriosis lesions 4 , 6 - 8 and NGF putative receptors, namely tyrosine kinase receptor A (TrkA) and p75, are expressed in nerve fibers innervating endometriosis lesions 62 . The TrkA receptor plays a well-established role in mechanical inflammatory and neuropathic hyperalgesia 39 . Reversible knock-down of receptors in nociceptors by intrathecal administration of antisense (AS) oligodeoxynucleotides (ODN) has been shown to be a reliable tool to assess their role in the processing of nociceptive information 57 . Injected intrathecally, AS ODN reach the soma of sensory neurons 11 , 31 , 32 , 57 and selectively inhibit the expression of proteins in these cells 28 , 30 , 59 and peripheral fibers 29 , 30 , 59 . Taking advantage of this approach, we assessed the contribution of IL-6, TNFα and NGF, which are pronociceptive mediators produced by endometriosis lesions 4 , 6 - 8 and surgical rat models of endometriosis 68 , by intrathecally administering to rats previously submitted to a model of endometriosis pain AS ODNs targeting mRNA of the TNF receptor 1 (TNFR1), the IL-6 receptor-signaling complex subunit glycoprotein 130 (gp130) and the tyrosine kinase receptor A (TrkA). Since the putative ligands for these receptors have been reported to induce a local mechanical hyperalgesia which is sensitive to intrathecal antisense treatment 18 , 19 , 39 , 47 , we evaluated their contribution to mechanical hyperalgesia observed in a surgical model of endometriosis by activating nociceptors innervating the endometriosis-like lesion.

Results

All rats recovered uneventfully from the surgery to implant uterine tissue onto the gastrocnemius muscle and developed cystic lesions, by our previously reported technique 2 . These changes were observed regardless of their estrus cycle status at the time of surgery. Fourteen days after surgery, the mechanical nociceptive threshold at the site of implanted ectopic uterine tissue was markedly decreased by 56.7 ± 0.8% compared to pre-surgical baseline (1100 ± 19.6 mN versus 2541 ± 5.6 mN, respectively; n = 38, P < 0.0001, Fig. 1A-C ). The contribution of the IL-6 released by ectopic uterine tissue in the endometriosis pain model was assessed by intrathecal injection of the AS (or the respective MM) ODN targeting the gp130 signaling subunit of the IL-6 receptor, for 3 consecutive days. Two-way repeated measures ANOVA showed significant effects for ODN treatment × time interaction ( F = 21.23; DFn = 4, DFd = 48, P < 0.0001), main effect of the ODN treatment ( F = 20.17; DFn = 1, DFd = 48, P = 0.0007) and time ( F = 329.7; DFn = 4, DFd =48, P <0.0001). Multiple comparisons analysis showed that mechanical hyperalgesia at the implant site was significantly attenuated by the AS-compared to the MM-ODN treatment on days 1 (1693 ± 77.1 mN [n=8] versus 1004.3 ± 62.8 mN [n=6], respectively; P < 0.001) through 5 (1182 ± 109.3 mN [n=8] versus 937 ± 49.5 mN [n=6], respectively; P < 0.05) after last injection of ODN ( Fig. 1A ). The contribution of TNFα released by ectopic uterine tissue in the endometriosis pain model was evaluated by injecting intrathecally the AS (or the respective MM) ODN targeting the TNFR1 for 3 consecutive days. The two-way repeated measures ANOVA showed a significant group x time interaction ( F = 5.28; DFn = 4, DFd = 48, P = 0.0013) and time ( F = 383.13; DFn = 4, DFd =48, P <0.0001), but not for main effect of ODN treatment ( F = 3.85; DFn = 1, DFd = 48, P < 0.0734). Multivariate analysis showed that mechanical hyperalgesia at the site of implant was significantly attenuated by the AS, but not by MM, only at the day 1 time point (1416 ± 60.7 mN [n=8] versus 1068 ± 91.4 mN [n=6], respectively; P < 0.05) after the last ODN injection ( Fig. 1B ). Finally, the contribution of NGF at the site of the ectopic uterine tissue was evaluated by injecting intrathecally an AS (or the respective MM) ODN targeting the TrkA receptor, for 3 consecutive days. The two way repeated measures ANOVA showed a significant group x time interaction ( F = 11.70; DFn = 4, DFd = 32, P < 0.0001), main effect of group ( F = 54.56; DFn = 1, DFd = 32, P < 0.0001) and time ( F = 402.96; DFn = 4, DFd = 32, P < 0.0001). Multivariate analysis showed that mechanical hyperalgesia at the site of implant was significantly attenuated by the AS, but not by MM, treatment on days 1 (1483.6 ± 115.6 mN [n=5] versus 1020.4 ± 45.6 mN [n=5], respectively; P < 0.001) through 3 (1419 ± 20 mN [n=8] versus 1012.4 ± 29.9 mN [n=5], respectively; P < 0.001) after last ODN injection ( Fig. 1C ).

Discussion

The pain associated with the growth of ectopic endometrium in patients with endometriosis is extremely common and can be severely disabling. Moreover, it is often resistant to available analgesic treatments, which in part reflects our lack of knowledge of underlying mechanisms mediating the pain of endometriosis. Therefore, in the present study we evaluated the involvement of mediators produced by endometriotic lesions in a preclinical model of endometriosis pain 2 , to determine inhibitors of which mediators might be useful leads for the development of novel mechanism-based analgesic strategies. The clinical characteristics of endometriosis pain suggest that mechanical hyperalgesia is the main underlying mechanism mediating pain in patients with this condition characterized by the presence of dysmenorrhea, dyspareunia, dysuria and dyschezia 24 , 54 , consistent with mechanically-evoked pain observed during intraoperatory exploration 34 . Surgical removal of endometriosis lesions provides an important degree of pain relief 66 , indicating an important role for primary mechanical hyperalgesia in endometriosis pain. In our initial description of the endometriosis pain model 2 we described the marked similarity between lesions derived from our ectopic uterine tissue model and clinical lesions of endometriosis. Indeed, these explants exhibit not only epithelial and stromal endometrial cells, and typical uterine structures (endometrial glands), but also display molecular markers (cytokeratin 18, vimentin) reported in human cases of endometriosis 2 . Furthermore, clinical cases of endometriosis affecting skeletal muscle are well reported 13 , 22 , 23 , 35 . Therefore, the assessment of local mechanical hyperalgesia in our model of endometriosis pain is a pertinent approach, allowing the exploration of mediators and mechanisms underlying pain at the site of lesion induced by implanting uterine tissue at an ectopic site 2 . Nociceptors are posited to play an important role in persistent pain by interacting with the sources of proalgesic mediators 53 . Importantly, lesions developing from ectopic uterine tissue are innervated by local nociceptors 2 , 41 , 68 , which express many receptors for mediators involved in mechanical nociception 62 , 68 . And, surgical excision of lesions, whose stimulation exacerbates pain, produces clinical alleviation of pain 66 . Since most of the proteins required by nociceptors are synthetized in their somas 49 , the intrathecal administration of AS ODN can be used to inhibit, reversibly, the expression of specific receptors 57 and prevents its peripheral role in nociception 19 , 29 , 30 , 59 . In the present experiments we used this approach to assess the role of pronociceptive mediators released from endometriosis-like lesions, in the mechanical hyperalgesia of a rodent model of endometriosis 2 . Increased levels of IL-6 in peritoneal fluid of endometriosis patients 20 , 51 , 64 , and in lesions 61 or peritoneal fluid 15 of rodents submitted to models of endometriosis have been reported. These observations are in good agreement with our finding that knock-down of the gp130 subunit of the IL-6 receptor signaling complex produced a marked inhibition of the mechanical hyperalgesia exhibited in rats submitted to our model of endometriosis pain. Indeed, IL-6 plays a well-established role in mechanical nociception by acting at its receptor on nociceptors to sensitize them, in many different tissues 18 , 37 , 59 , 67 . Furthermore, the signaling subunit gp130 is critical for the sensitizing effect of IL-6 on nociceptors 5 , 52 , which is consistent with the antihyperalgesic effect produced by the intrathecal administration of AS directed against gp130 observed here. Increased levels of TNFα in peritoneal fluid of patients with endometriosis have also been observed 9 , 21 , 56 , which have been reported to be correlated with pain 56 but not with the type of endometriosis lesions 16 , suggesting a role in endometriosis pain. Moreover, local injections of TNFα produce persistent mechanical hyperalgesia in rodents 47 and marked inflammatory reaction in humans 25 . Thus, the finding that AS ODNs targeting TNFR1 produced only mild and short lasting inhibition of the mechanical hyperalgesia in our model of endometriosis pain is somewhat surprising. An insufficient knockdown of TNFR1 is unlikely to explain such a lack of efficacy, since previous studies using the same sequence at doses even lower have consistently shown the inhibition of the expression of TNFR1 in peripheral nociceptors 47 and marked attenuation of mechanical hyperalgesia induced by injection of TNFα into peripheral tissue 19 . It is still possible that TNFα produces pro-algesic effects in endometriosis by indirect mechanisms, such as increasing the release of NGF 65 . Of note, clinical trials using anti-TNFα monoclonal antibodies have also shown a lack of efficacy for the relief of endometriosis pain 33 , 38 but, since clinical experience targeting TNFα is still limited, it cannot be excluded as a player in endometriosis pain. Transient knock-down of the high affinity NGF receptor TrkA produced a marked attenuation of mechanical hyperalgesia at the site of endometriosis-like lesions. This indicates that NGF released from the endometriosis-like lesion, likely contributes to the mechanical hyperalgesia exhibited by rats submitted to our endometriosis pain model. This is in line with previous reports about the expression of TrkA in nerve fibers innervating both, endometriotic lesions in humans 62 and endometriosis-like lesions in rats 68 . On the other hand, increased levels of NGF in peritoneal fluid of women affected by endometriosis have been reported 7 , 8 . And, exposure to peritoneal fluid of endometriosis patients produces neurite outgrowth in isolated dorsal root ganglion preparations, which is inhibited by an anti-NGF antibody 7 . While local injection of NGF has consistently shown to produce mechanical hyperalgesia in humans 17 , 55 , 60 and animals 26 , 39 , 44 , the expression of NGF in the peritoneal fluid of patients with endometriosis seems not to be proportional to pain levels 8 . Such a lack of correlation between pain and local NGF levels has been observed in humans 46 and animals 27 suffering from osteoarthritis, a condition where the pain is sensitive to monoclonal antibodies directed against NGF 14 . This might indicate that NGF acts synergistically with other pro-algesic mediators, its local levels not necessarily being representative of its full involvement in endometriosis pain. Equally, the potential role of non-canonical ligands acting on TrkA receptor cannot be ruled out in the nociceptive responses explored and its importance in the effect observed in the antisense TrkA knock-down experiments. For instance, it has been shown that some structurally diverse ligands generated in vivo can specifically interact with the same receptor to regulate inflammation 48 . Indeed, other neurotrophins than NGF, such as neurotrophins 3 and 4, can elicit some activation of TrkA 36 . In summary, changes in mechanical hyperalgesia observed after the knock-down of gp130, TrkA and TNFR1 in nociceptors of rats submitted to a model of endometriosis pain suggest that IL-6 and NGF, but not TNFα, play a major role in endometriosis pain. This experimental approach might be useful for the identification of the contribution of additional putative putative proalgesic mediators in endometriosis pain, as well as of proalgesic mediators in other pain syndromes in which there is thought to be a major contribution of pronociceptive mediators generated at sites at which patients experience pain (e.g., arthritis, colitis, cystitis and myositis). Finally, this approach could be used to validate variations on an established model such as comparing the important pronociceptive mediators in the present novel model of endometriosis in which the ectopic endometrial lesion is growing extraperitoneally in skeletal muscle with mediators responsible for pain the well-established intraperitoneal endometriosis model 41 , 58 .

Materials|Methods

Adult female Sprague Dawley rats (220–240 g; Charles River, Hollister, CA) were used in these experiments. They were housed in the Animal Care Facility at the University of California San Francisco, under environmentally controlled conditions (lights on 07:00–19:00 h; room temperature 21–23°C) with food and water available ad libitum . Upon completion of experiments, rats were killed by pentobarbital overdose followed by cervical dislocation. Animal care and use conformed to NIH guidelines (NIH Guide for the Care and Use of Laboratory Animals). The University of California San Francisco Committee on Animal Research approved all experimental protocols. Concerted effort was made to minimize number and suffering of experimental animals, in accordance with the principle of the minimal sample size stated in the Ethical Guidelines for investigations of Experimental Pain in Conscious Animals 69 . Details of the model of surgically-induced muscle endometriosis used here have been previously described 2 . We have previously provided evidence that the implant of autologous uterine tissue onto the gastrocnemius muscle, but not control surgical procedures, induces long lasting mechanical hyperalgesia 1 , 2 . We used the same surgical procedure to implant the ectopic uterine tissue and behavioral nociceptive evaluation here. We 2 and others 10 , 41 have provided evidence that lesions developed from ectopic uterine implants are innervated by nociceptors arising from the receptor tissue. Furthermore, these nociceptors display markers typically observed in nociceptors of the receptor tissue, indicating a neo-innervation of the ectopic tissue by these primary nociceptive afferents 2 , 10 , 41 . Briefly, female rats were pre-medicated with a mixture of ketamine hydrochloride and xylazine (80 and 6 mg /kg, s.c., respectively) and anesthesia was maintained with isoflurane (1 -1.5% in 99-98.5% oxygen). The right dorsal paravertebral area was infiltrated with 0.25% bupivacaine (Marcaine ® , Hospira, Lake Forest, IL) and, under aseptic conditions, an incision approximately 2 cm in length was performed and to expose and isolate the right uterine horn. After ligature of uterine blood vessels, a 1 cm segment was removed and immediately placed in a Petri dish containing 0.9% NaCl. The musculature of the dorsal abdominal wall was closed with single crossed stitches and the skin incision closed with horizontal mattress stitches. The excised uterine tissue was measured with a millimeter scale and opened longitudinally; a full thickness 3 × 3 mm square of uterine tissue was then removed and kept in physiologic saline. The implant was performed through an incision in the biceps femoris muscle allowing exposure of the underlying gastrocnemius muscle. The square of uterine tissue was sutured to the surface of the gastrocnemius muscle applying three to four single stitches using 5-0 nylon with the endometrial portion of the uterine tissue contacting the gastrocnemius muscle. After checking for hemostasis, the b. femoris muscle and the skin incisions were sutured separately with single stitches. The sham surgical procedure was similar but the uterus was left intact and not implanted on the surface of the gastrocnemius. Surgical procedures were performed regardless of the estrous cycle status of the rats. The phase of the estrous cycle was assessed pre-operatively, as reported previously (Alvarez et al., 2012). Immediately after the induction of anesthesia for surgical implant of ectopic endometrium, 30 μl of NaCl 0.9% was flushed 3-4 times into the vaginal cavity. The resulting fluid was then placed onto a slide and observed unstained at 100× magnification. The diagnostic criteria used to determine the phase of the estrous cycle was based on cellular type predominance, as previously described 40 . Mechanical nociceptive threshold in the site of surgical intervention was quantified using a digital force transducer (Chatillon DFI2; Amtek Inc., Largo, FL, USA) with a custom-made 7 mm-diameter probe 3 . The use of a probe with a tip diameter ≥ 2.6 mm allows reliable measurements of mechanical nociceptive threshold in subcutaneous tissue, even when overlying cutaneous hyperalgesia is present 45 . Rats were lightly restrained in a cylindrical acrylic holder with lateral slats that allows for easy access to the hind limb and application of the force transducer probe to the site of implantation, in the belly of the gastrocnemius muscle. The nociceptive threshold was defined as the force, in milliNewtons, required to produce a flexion reflex in the hind leg. Baseline withdrawal threshold was defined as the mean of 3 readings taken at 5-min intervals. Rats were briefly anesthetized with 2.5% isoflurane in 97.5% O 2 . Then, a 30-gauge hypodermic needle was inserted into the subarachnoid space, on the midline, between the L4 and L5 vertebrae and the injection of ODN performed (20 μl). Proper intrathecal injections were systematically confirmed by checking for a sudden flicking of the tail 43 . To determine the contribution of IL-6 produced by the endometriosis lesion, its effect on nociceptors was disrupted by attenuating the expression of the signal transducing molecule glycoprotein 130 (gp130), a subunit of the IL-6 receptor signaling complex, which is necessary for IL-6 receptor function 59 . The AS ODN sequence, 5’-TCC TTCCCACCTTCTTCT G-3’, was directed against a unique sequence of rat gp130 mRNA. The corresponding GenBank accession number and ODN position within the cDNA sequence are M92340 and 1834–1852, respectively 63 . The mismatch (MM) ODN sequence, 5’- T A CT A C T CAC A TTC A TC A G-3’, corresponds to the gp130 subunit antisense sequence with six mismatched bases (denoted by bold letters). The dose of ODN (80 μg) was based on prior studies showing decreases in gp130 protein in nociceptors 59 and completely attenuated the IL-6 induced mechanical hyperalgesia 18 . To determine the contribution to endometriosis pain of TNFα produced by the endometriosis lesion, knockdown of the expression of TNF receptor type-1 (TNFR1) in nociceptors was performed. The antisense oligodeoxynucleotide (AS ODN) sequence 5’-ACACGGTGTTCTGTTTCTCC-3’ directed against a unique sequence of rat TNFR1 was used. The mismatch ODN (MM ODN) sequence, 5’- AC C CG T TGTTC G GTT G CTCC-3’, with four bases mismatched (denoted by bold face). We have previously shown that this AS ODN against TNFR1, at a dose of 80 μg, markedly decreases TNFR1 protein in nociceptors 47 and completely prevents mechanical hyperalgesia induced by administration of TNFα into peripheral tissues 19 . To determine the contribution of NGF produced by the endometriosis lesion, its effect on nociceptors was disrupted by attenuating the expression of TrkA. The antisense ODN sequence, 5′-CATCAACGAAGTCACCAGACCG-3′ was directed against a unique sequence of rat TrkA. The corresponding GenBank accession number and ODN position within the cDNA sequence are M85214 and 121–142, respectively. The mismatch ODN sequence, 5′-CA A CA T CGAAGT G ACGAGACC G -3′, corresponds to the TrkA subunit antisense sequence with four bases mismatched (denoted by bold). A search of the NCBI database to Rattus norvegicus identified no other sequences homologous to that used in this experiment. We have previously shown that intrathecal administration of TrkA AS completely eliminated NGF-induced mechanical hyperalgesia 39 . Rats were intrathecally injected daily, with either AS or MM ODN (80 μg) against TNFR1, gp130 or TrkA mRNA for 3 consecutive days. The AS- and MM ODN primers were purchased from Invitrogen (San Francisco, CA). A paired Student’s t -test (two tailed) was used to compare pre and post-operative mechanical nociceptive threshold. The analysis of the effect of intrathecal treatment was made by means of a two-way repeated measures analysis of variance (ANOVA), with one within subjects-factor (time) and one between-subjects factor (intrathecal treatment with two levels, AS ODN or MM ODN). If the ANOVA showed a significant interaction, Bonferroni’s multiple comparisons tests were performed to determine the basis of the differences. Graph Pad Prism 5.0 (GraphPad Software, Inc., San Diego, CA, USA) was used to plot the graphics and to perform the statistical analysis. Data were plotted as mean ± S.E.M and statistical significance was set at P < 0.05.

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endometriosis

MeSH descriptors

Cytokines Endometriosis Pain Pain Analysis of Variance Animals Cytokine Receptor gp130 Cytokine Receptor gp130 Cytokine Receptor gp130 Cytokines Cytokines Disease Models, Animal Endometriosis Estrous Cycle Female Hyperalgesia Hyperalgesia Interleukin-6 Interleukin-6 Interleukin-6

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