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ANALGESIA

The Antinociceptive Response to Nicotinic Agonists in a Mouse Model of Postoperative Pain

From the Department of Anesthesiology, Columbia University, New York City, New York.

Address correspondence and reprint requests to Dr. Pamela Flood, Associate Professor, Department of Anesthesiology, Columbia University, 630 West 168th St., New York City, NY 10032. Address e-mail to pdf3{at}columbia.edu.

Abstract

BACKGROUND: Nicotine, the prototypical broad spectrum agonist at central nicotinic receptors, has analgesic action after surgery. Various subtype-specific nicotinic agonists have antinociceptive effects in animal models, but the response is highly dependent on the model tested. In an effort to determine what nicotinic subtypes might be targeted in future clinical studies, we tested agonists selective for 4β2 and 7 containing nicotinic receptors in a mouse model of postoperative pain.

METHODS: After paw incision, mice were tested for heat latency and pressure threshold before and after treatment with a dose range of ligands selective for 4β2 and 7 containing nicotinic receptors. To demonstrate that nicotine reduced nociceptive input in this model, the lumbar spinal cords of a subgroup of these mice were stained for the phosphorylated form if CREB.

RESULTS: Nicotine and metanicotine (4β2 selective) were fully effective as an analgesic in heat and pressure testing. The 7 partial agonist GTS-21 significantly increased the heat latency after surgery, but did not alter pressure threshold. The 7 selective antagonist methyllicaconitine decreased the efficacy of nicotine to increase heat latency but did not affect pressure threshold. The number of cells in the superficial dorsal horn with nuclei that stained for pCREB was double on the surgical side and the ratio was reduced by nicotine in a dose-dependent manner.

CONCLUSIONS: Our findings suggest that nicotine reduced nociceptive input to the superficial and deep dorsal horn. It also provides support for 4β2 and 7 nicotinic-mediated antinociceptive actions.

Nicotine, given as a nasal spray, has analgesic activity in patients after surgery.1 Broad spectrum nicotinic activation has well-known antinociceptive action in animal models.2 Other more subtype selective nicotinic agonists have been considered for use in clinical pain syndromes, but the effect of these drugs in animal models is variable and the mechanism of action is unknown. A diverse array of nicotinic ligands has been shown to modulate the nociceptive response in a variety of animal pain models. However, the effect of these drugs is highly dependent on the model tested. For example, spinally administered nicotine, cytisine, and epibatidine induced short-lived allodynic activity, but only epibatidine causes thermal antinociception when tested with a hotplate.3 In contrast, when tested with tail flick, both spinal nicotine and epibatidine had antinociceptive, but not pronociceptive, properties (Damaj, 1998 #10).4 Nicotinic agonists that are selective for receptors containing an 7 subunit are not antinociceptive in most models, but the 7 selective nicotinic agonist choline provides antinociception in the tail flick model5 after tibial nerve transaction6 and in inflammatory pain models.7 These complexities are perhaps to be expected in the nicotinic system where nicotinic receptors composed of different subunits provide presynaptic modulation to serotinergic, noradrenergic, -aminobutyric acid-ergic, glycinergic, and glutaminergic transmission in the spinal cord.8–12 The differences in drug action are likely related to the role of the specific nicotinic subtype in the neural network relevant to the pain model being used.

Postoperative pain is a combination of primary nociception, inflammatory pain, and both primary and secondary sensitization.13 Because we are interested in the activity of nicotinic agonists in the postoperative setting for potential human use, we tested nicotine and several subtype selective nicotinic ligands in a mouse model of incisional pain developed by Brennan et al.14 and modified for use in mice by Pogatzki et al.15 We tested the allodynic response to both heat and pressure, as the stimuli are likely transduced through different pathways. Thus, we tested the hypothesis that the antinociceptive action of nicotine can be mimicked by more subtype-selective nicotinic agonists in an animal model of postoperative pain.

METHODS

With the approval of the animal use and care committee at Columbia University, 270 female 129J mice (Jackson Laboratories, Bar Harbor, ME) at 6–10 weeks of age were used. Because of the nature of the experiment, each animal was only used for one test concentration. They were housed in groups of five and had free access to food and water. Animals were housed in an American Association of Laboratory Animal Care-approved facility. At the end of the experiments, all mice were killed with CO₂.

Surgical Procedure
Mice were anesthetized with 1.5%–2.5% isoflurane in oxygen until there was no response to a paw and tail pinch. Alcohol 70% was applied to the foot before the surgery began as an antiseptic measure. Following the procedure described by Pogatzki and Raja15 in mice, a 5 mm longitudinal incision was made with a no. 15 blade through the skin and fascia of the plantar foot. The incision started 2 mm from the proximal edge of the heel and extended toward the toes. The underlying muscle was elevated with forceps, leaving the muscle origin and insertion intact. Finally, the skin was apposed using a single absorbable suture, and the wound covered with an antibiotic ointment. The mice were allowed to recover from anesthesia for 2 h before behavioral testing. In pilot studies, nociceptive responses were stable by 2 h after the completion of anesthesia and surgery.

Behavioral Testing
Heat Withdrawal Latency
We measured hindpaw withdrawal latency (HPWL) in up to five unrestrained mice (per study day) housed individually in clear plastic chambers as described previously.16 The chambers rested on a clear glass plate. The glass plate was warmed to minimize body heat loss. To diminish exploratory activity, the mice were acclimated to this environment for at least 30 min before commencing the study. After acclimation, a movable source of radiant heat was applied from a lamp through an aperture under the glass plate to the hindpaw of the resting mouse. The testing stimulus was 15% of maximal and caused an average increase to 42°C on movement. An investigator blinded to treatment modality measured the time from the onset of the stimulus to the time the mouse moved the hindlimb.

Pressure Threshold
The mice were placed on an elevated mesh floor within clear plastic chambers. Again, to reduce exploratory activity, the mice were allowed to acclimate to this environment for at least 30 min before testing. von Frey filaments were pushed up through the mesh flooring and against each mouse’s hindpaw. Each von Frey filament is calibrated to a specific value of grams of force applied before bending. A response to a filament was identified as the withdrawal of the paw when pressure was applied for 1 s. The von Frey filaments were applied in order of increasing pressure until paw withdrawal occurred. The filament’s grams of bending force value and that of the previous filament were averaged, giving us the final value of bending force that could be tolerated by that individual mouse. These tests were performed multiple times to each paw to ensure accuracy. A maximum value of 15 g was applied as the mice typically weighed 20 g.

Immunohistochemistry
The mice were anesthetized with 1.5%–2.5% isoflurane and perfused intracardially with saline followed by 4% paraformaldehyde. The lumbar region of the spinal cord was dissected and soaked for 90 min in 10%, 20%, and 30% sucrose in 0.1 M PB solution. The spinal cord segments were cut on a sliding microtome (Bausch & Lomb, Rochester, NY) at a 50 µm thickness. The free-floating slices were collected in saline.

The spinal cord sections were mounted on subbed slides and allowed to dry overnight. After the segments were pretreated with 3% normal horse serum (Vector Laboratories, Burlingame, CA), they were incubated for 30–60 min in a rabbit polyclonal pCREB antibody (Santa Cruz Biotechnology, Santa Cruz, CA) diluted in phosphate buffered saline 1:50. The sections were then incubated in biotinylated anti-rabbit IgG (Vector Laboratories) and further processed using Vectastain Elite ABC kit (Vector Laboratories) according to the manufacturer’s instructions. Finally, the immunoprecipitates were developed with 3,3'-diaminobenzedine with nickel chloride added to produce a gray-black stain.

The sections were dehydrated and fixed with cover slips. The slides were viewed under 20x magnification where the number of p-CREB containing nuclei per micron were counted.

Drug Treatment
The mice were tested for baseline heat latency and von Frey threshold before surgery. Two hours after surgery, the mice were tested (HPWL and von Frey) to obtain their postoperative baseline. Mice who deviated by more than 20% from the mean postsurgical value were not used for analysis. Immediately afterward, the mice received an injection of test drug, nicotine (Sigma Aldrich, St. Louis, MO), metanicotine (Sigma Aldrich), 3-(4-hydroxy, 2-methoxybenzylidene) anabaseine (GTS-21; Gift of Roger Papke, University of Florida, Gainesville, FL), or nicotine in combination with methyllicaconitine (MLA) (Sigma Aldrich). GTS-21 is a selective partial agonist at 7 containing nicotinic receptors in rodents.17 MLA is a competitive antagonist that binds to 7 containing nicotinic receptors with nanomolar affinity.18 The doses used for nicotine were 0.5, 1.0, 1.5, 2.0, 3.0, and 5.0 mg/kg. Nicotine 7 mg/kg induced seizures and death. Metanicotine doses used were 10, 20, 50, 100, and 200 mg/kg. The doses of GTS-21 used in this study were 1.0, 5.0, 7.5, 10.0, and 20 mg/kg. The agonist drug doses tested where based on prior estimates of relative potency to nicotine19,20 and were expanded to achieve a full dose-response relationship. Doses higher than 20 mg/kg GTS-21 were not tested because of limited supply and apparent saturation of the dose-response curve. Finally, in studies of nicotine treatment in the presence MLA, a dose of 5 mg/kg was chosen as being saturating in other studies.5,7 The efficacy and potency of the nicotinic ligands used are found in Table 1.

Curve Fitting and Statistics
The data were fit with the equation, y = (A₁ – A₂)/(1 + (X/X₀)^P) + A₂, where A₁ is the maxima, A₂ is the minima, X is the concentration at 50% effect, and P is the steepness of the curve. The data are expressed as mean ± sem. The HPWL in the presence of nicotine and MLA could not be fit as above because only one data point was above baseline and it was not possible to determine the maxima. The difference between heat latency in the presence and absence of MLA was compared with a t-test, where P < 0.05 was considered significant.

RESULTS

After surgery, the latency for withdrawal from the heat stimulus was reduced from a cumulative average of 9.3 ± 0.1 s before surgery to 3.3 ± 0.1 s after surgery. Pressure threshold was reduced from 15 g to 1.25 ± 0.28 g. These values remained statistically unchanged over 3 days without treatment and recovered to baseline values by 7 days after surgery (data not shown). Nicotine, administered intraperitonially increased the latency for heat withdrawal in a dose-dependent manner (Fig. 1a). The ED₅₀ for nicotine was 2.9 ± 0.3 mg/kg. Nicotine also increased the threshold for pressure withdrawal (Fig. 1b). The ED₅₀ nicotine concentration to enhance pressure threshold was 2.3 ± 0.6 mg/kg. The effect of nicotine on the pressure sensitivity of the wound was nearly a step function and was maximal at 3 mg.

View larger version (22K): [in this window] [in a new window]   Figure 1. Antihyperalgesic effect of nicotine and metanicotine after surgery. (a) The latency to heat withdrawal increases in a dose dependent fashion in response to nicotine after surgery. A1 is 2.9 ± 0.8 s, A2 is 30 ± 0.3 s, X0 is 2.9 ± 0.3 mg/kg nicotine, and P is 2.2 ± 0.4. The average presurgical baseline is 9.2 ± 0.2 s. (b) The pressure threshold for withdrawal of the wounded paw is also increased by nicotine. A1 is 3.2 ± 1.2 g, A2 is 15 ± 4.0 g, X0 is 2.3 mg/kg nicotine, and P is 13.9 ± 25.5. The average presurgical baseline is 15 ± 0 g of pressure. (c) The 4β2 selective agonist metanicotine also increases the latency for withdrawal from a heat stimulus. A1 is 6.1 ± 1.8 s, A2 is 30 ± 7.7 s, X0 is 98.3 ± 36.4 mg/kg metanicotine, and P is 2.2 ± 1.1. The average presurgical baseline is 10.1 ± 0.2 s. (d) A1 is 2.4 ± 1.3 s, A2 is 15.0 ± 6.9 s, X0 is 20.5 ± 0.02 mg/kg metanicotine, and P is 34.6 ± 1.5. The average presurgical baseline is 15 ± 0 g of pressure. The dotted lines represent presurgical baseline heat latency or pressure threshold. n = 4–5 mice per concentration.

Metanicotine, the 4β2 selective nicotinic agonist was also fully effective in treating the pain evoked by heat and pressure (Figs. 1c and d). However, when compared with nicotine, metanicotine was much less potent. The ED₅₀ for metanicotine was 98.3 ± 36.4 mg/kg, and at 200 mg/kg the withdrawal latency to heat was nearly maximal. Metanicotine was also fully effective in reducing pressure threshold. Maximal effects were produced using doses as low as 40 mg/kg, with an ED₅₀ of 15.0 mg/kg ± 6.9 (Fig. 1d).

To determine the potential role of 7 receptor activation in the relief of postoperative pain, we studied the effect of the 7 selective partial agonist GTS-2122 and the 7 selective antagonist MLA.24 Treatment with GTS-21 induced a small statistically significant antinociceptive effect in response to heat but not pressure (Figs. 2a and b). At the highest dose of GTS-21 used (20 mg/kg), the heat withdrawal threshold did not return to the preoperative baseline but was significantly higher than postoperative control (Fig. 2a; ANOVA, P < 0.001).

View larger version (19K): [in this window] [in a new window]   Figure 2. Effect of the 7 nicotinic partial agonist GTS-21 and nicotine in the presence of the 7 selective antagonist methyllicaconitine (MLA) on heat and pressure sensitivity after surgery. (a) The latency to heat withdrawal has a small but dose-dependent increases in response to systemic GTS-21 treatment. A1 is 4.0 ± 0.6 s, A2 is 7.0 ± 0.1 s, X0 is 7.3 ± 0.1 mg/kg GTS-21, and P is 11.0 ± 4.0. The average presurgical baseline is 7.7 ± 0.2 s. The average presurgical baseline is 15 ± 0 g of pressure. (b) The pressure threshold for withdrawal of the wounded paw is not changed by GTS-21 at doses up to 20 mg/kg. (c) Treatment with the 7 nicotinic selective antagonist MLA (5 mg/kg) reduces nicotine’s antihyperalgesic action on heat latency. The heat latency is significantly shorter at higher doses of nicotine (3 and 5 mg/kg; t-test, P < 0.001). The average presurgical baseline is 10.1 ± 0.2 s. (d) The presence of MLA does not alter the antihyperalgesic response to pressure after surgery. The average presurgical baseline is 15 ± 0 g of pressure. The dotted lines represent presurgical baseline heat latency or pressure threshold. The range of mice per concentration is n is 4–10 animals per concentration studied.

To garner further evidence for participation of 7 containing nicotinic receptors in nicotine’s antinociceptive action, nicotine was given in combination with the selective 7 nicotinic antagonist, MLA at a saturating dose (5 mg/kg). Similar to the pattern found with the 7 partial agonist, only the response to heat was reduced by MLA. The response to the two highest concentrations of nicotine was reduced in the presence of MLA (Fig. 2c; t-test, P < 0.001). In contrast, MLA did not alter nicotine’s antinociceptive action in the pressure response (Fig. 2d).

The reduction in response latency to heat and threshold for pressure around the wound may have been a result of decreased nociceptive input. The cells in the dorsal horn of the spinal cord are activated by nociceptive input after surgery, as demonstrated by significantly more phosphorylated CREB in the dorsal horn ipsilateral to the surgery when compared with the contralateral side. Figure 3a depicts a lumbar spinal slice stained for pCREB. The ratio of cells, which have nuclei positive for the phosphorylated form of CREB (ipsilateral/contralateral to the surgical site), is 1.8 in the superficial dorsal horn and 2.1 in the deep dorsal horn. Treatment with nicotine reduced the pCREB ratio in a dose-dependent manner (Fig. 3b) There was no change in pCREB after sham surgery or with nicotine treatment in the ventral spinal cord.

View larger version (43K): [in this window] [in a new window]   Figure 3. The effect of nicotine on phosphorylation of the immediate early gene, CREB in the dorsal horn of the spinal cord. (a) Spinal cord slice stained for pCREB. (b) Phosphorylation of CREB in the superficial dorsal horn on the side ipsilateral to the surgery is 1.8 times higher than on the contralateral side to the surgery. In the deep dorsal horn, phosphorylation of CREB is 2.1 fold higher on the ipsilateral side. Nicotine reduces CREB phosphorylation in a dose-dependent manner with an ID50 of 0.8 ± 0.1 mg/kg in the superficial dorsal horn and 0.8 ± 0.2 mg/kg in the deep dorsal horn. The dotted line represents pCREB levels from the sham condition. The number of mice per concentration is 3.

DISCUSSION

Nicotine reduced hyperalgesia after surgery in response to both heat and pressure stimuli. Because these behavioral tests require intact sensory and motor elements, we measured CREB phosphorylation as an indicator of neuronal activation in the dorsal horn. CREB phosphorylation was approximately doubled in the dorsal horn on the surgical side. The pCREB ratio (surgical/control side) was reduced by nicotine in a dose-dependent manner, suggesting that nicotine reduces nociceptive activation in the dorsal horn. Treatment with the 4β2 selective nicotinic agonist metanicotine also resulted in antihyperalgesia, but the response to pressure was more potent than that to heat. Clearly activation of 4β2 type nicotinic can provide analgesia in the postsurgical setting.

Activation of 7 nicotinic receptors reduces pain evoked by heat, but not pressure. The fact that GTS-21 was not fully effective to reverse allodynia was not unexpected, as GTS-21 is a partial agonist at 7 nicotinic receptors and would be expected to block excitation at higher concentrations. Additional evidence for a modulatory role for 7 nicotinic receptors comes from the fact that the efficacy of nicotine in heat-evoked responses is reduced in the presence of the 7 selective antagonist MLA. Again, it is not surprising that only the highest concentrations of nicotine tested would be affected by MLA, as 7 nicotinic receptors have lower affinity for nicotine than other heteromeric nicotinic receptors.25 One day after hindpaw incision in rats, there is spontaneous activity of C-fibers.26 The treatment of allodynia evoked by heat, but not by pressure, may suggest that activation of 7 nicotinic receptors plays a role in a pathway that involves C-fibers, but not A-fibers, because in studies in postoperative rats the response to monofilaments was enhanced only in A- but not C-fibers.

The 7 receptors whose activation is antihyperalgesic might be part of an inhibitory synapse within the peripheral nervous system or within the spinal cord. There is evidence for presynaptic 7 nicotinic receptors that control the release of norepinephrine30 in the lumbar spinal cord as well as serotonin.27 Another possibility is that 7 activation might reduce nociceptive input through a non-neuronal peripheral mechanism. Macrophages and microglia express 7 nicotinic receptors.28,29 The activation of these 7 receptors with nicotinic agonists decreases expression of inflammatory cytokines including tumor necrosis factor-. It is possible that decreased inflammation in the wound or in the central nervous system would result in decreased sensitivity to pain. In the setting of injury, 7 nicotinic receptor activation may provide a novel method for treating pain.

Footnotes

Accepted for publication November 30, 2007.

Dr. Flood is the wife of Dr. Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by Tony Yaksh, Section Editor of Pain Mechanisms, and Dr. Shafer was not involved in any way with the editorial process or decision.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rowley, T. J. Articles by Flood, P. Search for Related Content PubMed PubMed Citation Articles by Rowley, T. J. Articles by Flood, P. Related Collections Mechanisms Pain Mechanisms Preclinical Pharmacology Pain Pharmacology