- Open Access
Perineural resiniferatoxin selectively inhibits inflammatory hyperalgesia
© Neubert et al; licensee BioMed Central Ltd. 2008
- Received: 14 September 2007
- Accepted: 16 January 2008
- Published: 16 January 2008
Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a large body of evidence supporting a role for TRPV1 in noxious-mediated and inflammatory hyperalgesic responses. In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was inhibition of inflammatory hyperalgesia. Recovery studies showed that physiologic sensory function could return as early as two weeks post-RTX treatment, however, immunohistochemical examination of the DRG revealed a partial, but significant reduction in the number of the TRPV1-positive neurons. We propose that this method could represent a beneficial treatment for a range of chronic pain problems, including neuropathic and inflammatory pain not responding to other therapies.
- Dorsal Root Ganglion
- Sciatic Nerve
- Neurogenic Inflammation
- Saphenous Nerve
Resiniferatoxin (RTX), an ultrapotent capsaicin analog, is a vanilloid agonist that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1), a non-selective cation ion channel expressed in small- and medium-sized neurons in sensory ganglia [1–3]. Evidence from TRPV1 gene deletion studies supports a role for TRPV1 in noxious thermal, chemical, and inflammatory hyperalgesic responses [4, 5]. Behaviorally, long duration noxious heat analgesia can be induced by subcutaneous RTX administration [6–9]. These data reinforce the long-recognized idea that TRPV1 has an important role in inflammation and pain and thus TRPV1 has become a target for analgesic drug development [10–16].
Vanilloids can trigger a Na+/Ca2+ flux in axons of primary cultured dorsal root ganglia (DRG) neurons . We have observed that when RTX is administered in close proximity to the cell body of TRPV1-positive neurons (i.e., intra-ganglionic), it induces a Ca2+-excitotoxicity and subsequent permanent neuronal cell deletion [18, 19]. This route of application has been proposed as a treatment for pain in advanced metastatic disease [9, 20, 21]; however, a reversible approach for achieving analgesia represents an alternative route with certain advantages for pain control in non-malignant situations. Based on prior studies using peripheral application of vanilloid agonists such as capsaicin and RTX [8, 22–25], we hypothesized that perineural application of RTX may temporarily block transmission in TRPV1-containing axons. The percutaneous perineural approach is proposed to broadly target a specific nerve and its' peripheral receptive fields to produce a selective antinociceptive action while maintaining other somatic and proprioceptive sensations conveyed by large diameter TRPV1-negative axons. By modifying transmission through the peripheral nerve, this method can provide analgesia in a wide range of chronic pain problems. Perineural application has recently been explored using high doses of RTX (1500 ng) to eliminate thermal and inflammatory heat sensitivity and reduce motor reaction threshold responses to pressure . However, in the clinical setting, exploration of the lower range of doses needs to be considered in order to determine the minimum effective dose for analgesia that reduces or eliminates potential side effects. In the present study, we investigate the efficacy of lower doses of RTX and evaluate the temporal recovery of function by using perineural RTX against acute pain challenges and evaluate its effectiveness in preemptively blocking inflammation-induced hyperalgesia.
All procedures complied with the guidelines of the Committee for Research and Ethical Issues of IASP and the Institutional Animal Care and Use Committee of the National Institute of Dental and Craniofacial Research, National Institutes of Health.
RTX or vehicle application
While the sciatic nerve innervates the majority of the hindpaw, a small part of the medial plantar surface of the hindpaw is also innervated by the saphenous nerve and the stimulus can overlap to this receptive field. Therefore the saphenous nerve was additionally injected in a subset of animals (N = 15) to evaluate the effects of RTX when applied to both the sciatic and saphenous nerves. Following percutaneous sciatic nerve injection (see above), a 0.5 cm incision was made into the medial aspect of the leg at the mid-thigh level and RTX (250 ng, 50 μl) was injected directly onto the saphenous nerve. A single Vicryl resorbable (4-0, Ethicon) suture was used to close the wound and topical triple antibiotic cream (Neomycin, Polymyxin B, and Bacitracin ointment, USP) was applied.
To further assess the efficacy of the percutaneous approach, we examined a group of animals (N = 10) that received RTX via a direct, open surgical procedure. Animals were anesthetized, surgically prepared as described above, and a 1 cm incision was made through the skin at the mid-thigh portion of the hind limb. The underlying gluteus superficialis muscles were bluntly dissected and the sciatic nerve exposed. The overlying fascia was carefully removed and RTX (250 ng, 50 μl) was bathed over 1 cm of the nerve for 5 min, after which the wound was closed with Vicryl resorbable (4-0, Ethicon) sutures and the animals were allowed to recover. Note that the RTX solution was not washed off prior to suturing the area to better simulate the exposure produced via the percutaneous injection method.
To determine the flow and uptake of fluid to and around the sciatic nerve, Fluorescein-5-isothiocyanate (FITC, 'Isomer I', 0.05 mg in 50 μl PBS, Molecular Probes, Eugene, OR) was injected into a subset of animals (N = 2) to verify targeting of the sciatic nerve (Fig. 1B). Animals were sacrificed (CO2 inhalation) and the injected sciatic nerve was dissected free, cut in cross-section (5 μm), formalin fixed and paraffin embedded. Sections were visualized under an Olympus BX-60 microscope equipped with a RT-Slider CCD camera (Diagnostic Instruments Inc. Burroughs, MI), using the appropriate filters and the Spot Advance software.
Development of heat hyperalgesia and analgesia to radiant thermal stimulation was determined by placing unrestrained animals under a small plastic box (9 × 6 × 6 in) on an elevated clear glass platform, as described previously [26, 27]. Animals were allowed to habituate for at least 5 min prior to testing. Testing was performed prior to injection, and at various time points (2.5 hrs, 1 day, 1 week, 2 weeks, 1 month, 3 months, 6 months) following the nerve injection and 2.5 hrs after hindpaw carrageenan injection. Statistical analyses (one-way and two-way repeated measures ANOVA with Scheffe post-hoc analysis) were used to compare baseline withdrawal latency times to post-treatment times and treated versus untreated values.
Sensitivity to mechanical stimuli was evaluated using an electronic Von Frey anesthesiometer (Model 1601, IITC Inc, Woodland Hills, CA). Following placement of animals under the plastic box on an elevated open-grated surface and habituation (5 min), the probe tip was applied perpendicularly to the ventral paw surface and pressure was applied until the animal withdrew its paw. The average force (gm) to elicit paw withdrawal was calculated from three iterations (5 min between each trial). Raw threshold values were normalized to the initial baseline values (base) and time and treatment effects were analyzed using a Mann-Whitney rank sum test or Kruskal-Wallis ANOVA (P < 0.05 significance). Effects on gross behaviors (grooming, limb guarding, and licking) following RTX injection were also assessed.
Gross motor impairment was evaluated using a rotarod apparatus (Model 7650, Ugo Basile, Comerio VA, Italy), as described previously . The time (sec) required for the animal to fall off an accelerating rotating wheel drum (4–40 r.p.m. in 5 min) was recorded and time and treatment (RTX or vehicle) effects were analyzed using one-way ANOVA and two-way repeated measures ANOVA (p < 0.05).
Inflammation and paw thickness measurements
Carrageenan (6 mg, Sigma, St Louis, MO) was injected (150 μl, i.pl.) into the mid-plantar surface of the hindpaw of unanesthetized rats as described previously . Inflammation was initiated at the following post-injection (RTX or vehicle) time points: 1 day; 1 week; 2 weeks; 1 month; 3 months; and 6 months. Paw thickness was also measured at the mid-hindpaw level before and after carrageenan inflammation for a subset of animals pretreated with either RTX (N = 5) or vehicle (N = 5); the difference (mm) from pre- to post-inflammation was calculated.
Animals were assessed 1 week after perineural RTX or vehicle injection. Following anesthesia (pentobarbital, 50 mg/kg, i.p.), the hair from the right and left rear legs was completely removed using a depilatory cream (Nair, Carter-Wallace, Inc, Cranbury, NJ). A PE10 catheter was placed in the jugular vein and Evans Blue (EB, Sigma, St. Louis, MO) was infused over 10 min (30 mg/kg; 2% solution, i.v). Capsaicin cream (1%) was liberally and evenly applied to the legs and to the dorsal and plantar surfaces of both hindpaws and digital pictures were captured (Sony MVC-FD100 FD Mavica digital still camera).
Animals were deeply anesthetized (pentobarbital, 100 mg/kg, i.p.) 31 days post-RTX injection and fixed by transcardial perfusion with cold phosphate buffered saline (PBS) followed by cold Streck's Tissue Fixative (STF). Right and left lumbar 4–5 (L4-L5) dorsal root ganglia (DRG) were dissected and placed in STF for post-fixing. Samples were paraffin processed and sections were cut (7 μm) and mounted on slides. Following deparaffinization and epitope unmasking with Target Retrieval Solution (S1700, Dako, Carpinteria, CA) at 95°C for 20 min, sections were blocked with 10% normal goat serum (S-1000, Vector Laboratories, Inc., Burlingame, CA) and incubated overnight at 4°C with the TRPV1 primary antibody (1:10,000, Oncogene, #PC420). Antibody detection was performed using the Vectastain Elite Rabbit IgG and Peroxidase Substrate Kits (SK-4700 and SK-4100, respectively, Vector Laboratories, Inc., Burlingame, CA). Sites of peroxidase activity were visualized using 3,3'-diaminobenzidene tetrahydrochloride (DAB). Control specimens for assessment of non-specific binding were processed in an identical way except for omission of the primary antibody. Histological sections were visualized with an Olympus BX 60 microscope, equipped with a RT Slider CCD camera and processed with the Spot Advanced software.
A total of N = 7 animals were used for the histological analysis: N = 5 animals had RTX (250 ng, 50 μl) applied to the left sciatic nerve and vehicle (0.25% Tween 80 in PBS, 0.05% ascorbic acid, 50 μl) applied to the right sciatic nerve. A total of N = 10 DRG were examined for each treatment from these 5 animals and a blinded observer chose non-adjacent sections (separated by > 100 μm) from different levels of the DRG for each treatment group to give a final N = 15 sections/group. The remaining N = 2 untreated naïve animals had 2 DRGs harvested from each, with a total of N = 6 sections counted. The number of TRPV1 immunoreactive and non-immunoreactive cell bodies within a rectangular reticule were counted by visual inspection (10× magnification); the ratio of TRPV1 to the total number of cells was calculated and comparisons between treatment groups (RTX, vehicle, no treatment) were performed using a one-way ANOVA and Scheffe post-hoc test, with significance set at a level of P < 0.05.
Behavioral observations and effects on inflammatory edema
We were interested in assessing general behavioral and anti-inflammatory effects of perineural RTX. Following injection (RTX or vehicle) and recovery from anesthesia (< 10 min), animals did not display nociceptive behaviors, such as licking, guarding, which we had observed in previous studies upon injection into the hindpaw (Neubert 2003). We also never observed abnormal behaviors such as autotomy in any of the animals, such as seen with complete sciatic denervation . Perineural RTX did not affect paw edema following carrageenan inflammation (change in hindpaw size was 6.2 ± 0.3 mm for RTX, 6.0 ± 0.2 mm for vehicle). These data indicate that the doses of RTX used for analgesia did not inhibit the inflammatory stimulus provided by the carrageenan injection.
RTX blocks inflammatory heat hyperalgesia when applied directly to the sciatic nerve in a time and dose dependent fashion
RTX inhibited inflammatory heat hyperalgesia in a dose-dependent fashion, with the effective dose being ≥ 125 ng (Fig. 4B). The lower doses did not significantly block inflammatory hyperalgesia, as compared to vehicle. For the 250 ng group following inflammation, there was no significant difference compared to pre-inflammation values, and these groups had significantly higher values as compared to doses of 62.5 ng and lower. We chose to use the 250 ng dose throughout the rest of the study to minimize variability in responses at the lower effective dose (125 ng). There were no significant differences between any of the doses and vehicle on pre-inflammatory heat withdrawal latency for these sets of animals (Fig. 4B).
Mechanical sensitivity and rotarod responsiveness
Rotarod results demonstrate that there were no significant differences between animals that received vehicle or RTX perineurally next to the sciatic nerve when comparing the duration (sec) the animals remained on the accelerating rotating rod (Fig. 5B). Moreover, the increase in rotarod performance over the testing times was similar for both groups, suggesting that comprehensive or delayed motor problems did not develop. Note that data derived from the accelerating rod test provides a sensitive measure for minor coordination problems since it forces both control and treated rats to perform to the point of failure. Deficits that the rat can compensate for in a slowly moving rod are revealed using the accelerating paradigm.
Perineural RTX partially depletes TRPV1- immunopositive cells in sensory ganglia
RTX blocks neurogenic inflammation (Fig. 7)
RTX eliminated the plasma extravasation following neurogenic inflammation induced by topical capsaicin cream (Fig. 7). In all animals, a clear demarcation demonstrating an effect on the peroneal division of the sciatic nerve is noted on the lateral aspect of the hind leg (A) and on the dorsum of the lateral two toes of the hindpaw in animals treated with RTX (C). The medial blue extravasation indicates that the saphenous nerve was spared during the RTX treatment, therefore this region was not protected from the capsaicin-induced neurogenic inflammation. The animal illustrated is typical of seven rats tested for plasma extravasation in which only the sciatic nerve was treated.
The selective analgesic approach to pain control without the loss of other functions has been the focus of many laboratories. For example, targeting of sodium channels such as NaV 1.8 has led to development of antagonists in the quest for novel analgesics (Veneroni et al, Pain 2003). TRPV1 antagonists have been shown to be effective for reducing chemical, thermal, and inflammatory pain without significant motor effects (Garcia-Martiez et al PNAS 2002, Gavva et al, JPET 2005). In this study, we demonstrated that perineural application of RTX produces a dose- and time-dependent inhibition of inflammatory nociceptive processes, while maintaining normal proprioceptive sensations and motor control. Remarkably, most other pain sensations were preserved except for the change in inflammatory heat hyperalgesia. There was a small but statistically significant effect on the response to mechanical stimuli when comparing RTX-treated animals with vehicle-treated animals following inflammation (Fig. 5). However, in reference to pre-inflammatory testing sessions, the difference between RTX- and vehicle-treated animals does not appear to be substantial (Fig. 5). Additional application of RTX to the saphenous nerve did not significantly affect the anti-inflammatory hyperalgesia response as compared to application to the sciatic nerve alone, although application to both the saphenous and sciatic nerves did increase the normal thermal latency (Fig. 2). However, sciatic perineural application may be sufficient for producing regional effects while maintaining normal thermal, mechanical, and proprioceptive sensations. We demonstrate a blockade of neurogenic inflammation mediated by the sciatic nerve with this percutaneous approach (Fig. 7) based on plasma extravasation in peripheral receptive fields. We observed a significant reduction of inflammatory hyperalgesia which was the most sensitive nociceptive endpoint.
Jancso and Lawson demonstrated that capsaicin applied to the saphenous nerve produced a loss of approximately a third of the unmyelinated fibers compared to control nerves, while the proportion of myelinated fibers remained unchanged . Additionally, this group found that perineural capsaicin application produced a reduction in the proportion of small-sized neurons in the ipsilateral DRG. Similarly, in this study, we found a significant loss of TRPV1-positive cells following perineural RTX application in the corresponding DRG one month following treatment, but based on the behavioral outcomes, larger myelinated nerve fibers appeared to be unaffected by RTX. Furthermore, even with this permanent cell loss we observed a recovery of inflammatory hyperalgesia beginning approximately 2 weeks after injection. This is consistent with several possibilities: (a) functional repair of the RTX-affected axons occurs after that time, (b) there could be a return of function due to collateral sprouting of un-injured axons into the denervated paw, (3) sensitivity of the existing axons could be enhanced. The cell loss may impact other general functions but we did track a set of animals for 6 months and these animals displayed normal behaviors throughout. This is consistent with the Karai et al study that demonstrated no adverse events for up to a year following intra-trigeminal ganglia injection . The mechanism for functional recovery and long-term effects will be the subject of a follow-up study.
Targeting of primary afferent nociceptive transmission at the peripheral axons provides an approach for producing regionally specific therapeutic effects [9, 24, 25, 30]. Earlier studies using capsaicin demonstrated that direct application to peripheral nerves produced transient nociceptive activity, followed by a prolonged inhibition of responses to noxious stimuli, especially heat and inhibition of neurogenic inflammation [23, 31, 32]. However in this context, capsaicin produced permanent impairment of a proportion of C-fibers in sensory nerves as these capsaicin treated rats continued to exhibit a deficit when tested between 3–12 months [23, 33]. In contrast, we demonstrate recovery of sensitivity to inflammatory hyperalgesia with RTX between 2 weeks and 6 months, suggesting the more potent agent has fewer non-specific toxic side effects. The specificity of RTX is further supported by preservation of motor and mechanical sensitivity, as demonstrated in this study (Fig. 5) and previously . This is not a feature of studies performed with higher doses of RTX which reported deficits in mechanical endpoints .
Based on our study with intradermal application of RTX, we selected a dose range for RTX from 25 – 250 ng  and evaluated these doses for analgesia and potential side effects. We found that for perineural application of RTX there was a steep dose response relationship occurring between 62.5 and 125 ng, with doses ≥ 125 ng able to significantly block the hyperalgesic response to inflammation (Fig. 3). We used the 250 ng dose of RTX throughout the remainder of the study to reduce variability in responses at the lower doses. In the absence of concurrent inflammation, we observed that animals were able to respond normally to noxious thermal stimuli (Fig. 2). We also noted that there were no obvious effects on the edema produced following carrageenan inflammation when pretreated with RTX, as compared to vehicle. While the neurogenic component of inflammation was eliminated, there are other signs of inflammation such as edema that suggest other inflammatory pathways are not suppressed by RTX. While this animal model suggests that it may not show efficacy in reducing mechanical allodynia, this should not exclude the potential therapeutic action in human pathological pain states, since some of these pain states can be maintained by peripheral inputs. Others have shown that higher doses of RTX given in a variety of routes are effective for reducing nociception [7, 24]. Kissin et al described a more broad-spectrum effect of RTX administered percutaneously to the sciatic and saphenous nerves and showed decreased sensitivity to normal and inflammatory mechanical and heat hyperalgesia . However at the doses used in that study (1,500 ng), systemic or non-specific effects of RTX cannot be ruled out and may confound the utility for translation into clinical pain control. Recently this group demonstrated reduction of incisional post-operative pain with perineural treatment of the sciatic and saphenous nerve using a lower dose of RTX (450 ng), supporting our contention that smaller amounts of RTX are sufficient for pain control.
Thermal sensing channels, in particular TRPV1, provide targets for discovering new pain therapeutics [34, 35]. The use of TRPV1 agonists such as RTX represents an exciting approach for management of pain clinically especially using site-directed application methods [8, 9]. In the current study, we found that an anatomically directed perineural application of RTX, blocked inflammatory hyperalgesia, while sparing normal somatosensory input, including thermal and mechanical modalities. As such, localized application of RTX has the potential for a range of uses in pain management, from acute post-operative care to treatment of regional pain disorders.
Support from this research was provided by the Division of Intramural Research, and from grant #1K22DE014865-01A1, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA, and NIDCR.
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