PREGABALIN

Formulation

The table below describes the formulation of pregabalin and the controls morphine sulfate, gabapentin, and oxycodone hydrochloride for the following in vivo experiments.

Experiment(s)	Compound	Dose(s) mg/kg	Correction factor	Dose volume mL/kg	Route	Vehicle	Suspension / Solution
Pharmacokinetics	Pregabalin	30	1.00	1	PO	Saline	Solution
Irwin, Rotarod	Pregabalin	10, 30, 60, 100	1.00	5	PO	Saline	Solution
Plantar incision, MIA,	Pregabalin	10, 30, 60	1.00	5	PO	Saline	Solution
Paclitaxel CIPN,
Oxaliplatin CIPN
L5/L6 SNL	Pregabalin	10, 30, 60	1.00	1	PO	Saline	Solution
CPP	Pregabalin	3, 10, 30, 100	1.00	1	IP	Saline	Solution
IVSA	Pregabalin	0.1, 0.3, 1, 3	1.00	0.088 mL/infusion	IV	Saline	Solution
IVSA	Pregabalin	mg/kg/infusion	1.00	0.088 mL/infusion	IV	Saline	Solution
Plantar incision,	Morphine	6	1.33	1	SC	Saline	Solution
L5/L6 SNL (Acetone), MIA,
Paclitaxel CIPN,
Oxaliplatin CIPN
L5/L6 SNL (von Frey)	Gabapentin	60	1.00	1	PO	Saline	Solution
CPP	Oxycodone	3	1.12	1	IP	Saline	Solution
IVSA	Oxycodone	0.06	1.12	0.088 mL/infusion	IV	Saline	Solution
IVSA	Oxycodone	mg/kg/infusion	1.12	0.088 mL/infusion	IV	Saline	Solution

MIA = monosodium iodoacetate, L5/L6 SNL = L5/L6 spinal nerve ligation, CPP = conditioned place preference, IVSA = intravenous self-administration, PO = per os, IV = intravenous, SC = subcutaneous, IP = intraperitoneal

Results

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Method: Protein binding

A table shows the results of rapid equilibrium dialysis to assess protein binding and percent recovery of pregabalin. In rat plasma, pregabalin was 4.2% bound to protein and 95.8% unbound and had a recovery of 123.7%. In rat brain homogenate, pregabalin was 7% bound to protein and 93% unbound and had a recovery of 124.1%. Acebutolol, quinidine, and warfarin were included in the study as controls and returned values consistent with literature values.

Method: Pharmacokinetics

Animals were randomly assigned to treatment groups.

Experimenters collecting samples were masked to treatment.

Pregabalin concentrations were measured in serially collected plasma samples and terminally collected brain samples (shown on two graphs) from males and females treated with 30 mg/kg pregabalin (PO) in a vehicle of saline. There were 4 rats/group for plasma and 3-4 rats/group for brain.

Method: Pharmacokinetics

A table shows pharmacokinetics parameters calculated for pregabalin using non-compartmental analysis in male and female rats treated with pregabalin (30 mg/kg, PO, vehicle of saline). The means for the 2 groups (males and females treated with 30 mg/kg pregabalin, respectively) are as follows. The highest concentration (Cmax) was 61.1 and 60.4 µM; the time at the maximum concentration (Tmax) was 1 hour for each group; the half-life (T1/2) was 4.25 and 4.4 hours; area under the curve for time 0 to 24 hours was 474 and 428 minutes*µM; area under the curve for time 0 to infinity was 485 and 438 minutes*µM; the brain-to-plasma ratio at 1 hour was 0.13 and 0.18; the brain-to-plasma ratio at 24 hours was 0.37 and 0.36.

Method: Modified Irwin functional observational battery

Animals were balanced across treatment groups based on body weight.

Experimenters assessing behavior were masked to treatment.

Group size was determined using power analysis.

Two reviewers observed and scored 39 behaviors in a modified Irwin test. For each animal, the scores for behavioral observations from each reviewer are summed then averaged for male and female rats (shown on two graphs). Responses are shown at the following time points: baseline (before treatment) and at 1, 2, 4, and 6 hours after treatment with vehicle (saline, delivered PO) or pregabalin (10, 30, 60, or 100 mg/kg, delivered PO). There were 4 rats per group. Kruskal-Wallis tests were performed at each timepoint for each sex, followed by Dunn’s tests when a significant effect was observed. Dunn’s tests found an increase in the number of observations relative to vehicle in males at 1 hour post-treatment with 60 mg/kg pregabalin (p<0.05) and 100 mg/kg pregabalin (p<0.05), at 2 hours post-treatment with 60 mg/kg pregabalin (p<0.05) and 100 mg/kg pregabalin (p<0.05), at 4 hours post-treatment with 100 mg/kg pregabalin (p<0.01), and at 6 hours post-treatment with 60 mg/kg pregabalin (p<0.05). Dunn’s tests found an increase in the number of observations relative to vehicle in females at 2 hours post-treatment with 60 mg/kg pregabalin (p<0.05) and 100 mg/kg pregabalin (p<0.01), at 4 hours post-treatment with 60 mg/kg pregabalin (p<0.05) and 100 mg/kg pregabalin (p<0.05), and at 6 hours post-treatment with 60 mg/kg pregabalin (p<0.05). Data were analyzed using GraphPad Prism version 10.0.2

Method: Modified Irwin functional observational battery

A heat map depicts the severity of the behaviors observed by two reviewers in a modified Irwin test at baseline and at 1, 2, 4, and 6 hours following the administration of vehicle (saline, delivered PO) or pregabalin (10, 30, 60, or 100 mg/kg, delivered PO). There were 8 rats per group (4 male and 4 female). Severity score was calculated as the sum of scores given by the two reviewers for all animals at that dose and timepoint divided by the maximum possible score, transformed into a percentage. In summary, pregabalin administration produced effects including decreased body position and sedation in a dose- and time-dependent manner.

Method: Modified Irwin functional observational battery

Two graphs show the body temperature of male or female rats during the modified Irwin test. Responses are shown at the following timepoints: baseline (before treatment) and at 1 and 6 hours after treatment with vehicle (saline, delivered PO) or pregabalin (10, 30, 60, or 100 mg/kg, delivered PO). There were 4 rats per group. A significant effect of time was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found a significant decrease in body temperature at 6 hours post-treatment in males (p<0.01) and females (p<0.001) relative to baseline of the same sex. Data were analyzed using GraphPad Prism version 10.0.2

Method: Rotarod

Animals that achieved a latency of 40 seconds during the baseline trial were included in the study.

Two graphs show the latency for male or female rats to fall off a rotarod apparatus. Responses are shown at the following time points: baseline (before treatment) and at 1, 2, 4, and 6 hours after treatment with vehicle (saline, delivered PO) or pregabalin (10, 30, 60, or 100 mg/kg, delivered PO). There were 10 rats per group. Neither males nor females had a significant interaction of time x treatment in a two-way repeated measures ANOVA, but a significant effect of treatment was found for each sex. Bonferroni’s tests found a significant decrease in the latency to fall relative to vehicle in males after treatment with 60 mg/kg pregabalin (p<0.01) and 100 mg/kg pregabalin (p<0.0001). Bonferroni’s tests found a significant decrease in the latency to fall relative to vehicle in females after treatment with 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.05), and 100 mg/kg pregabalin (p<0.0001).

Model: Plantar Incision Model in Rat (Brennan Model)

Animals were balanced across treatment groups based on body weight and post-surgery withdrawal thresholds.

Animals with ipsilateral post-surgery withdrawal thresholds ≤3.0g were included in the study.

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Two graphs show ipsilateral hind paw mechanical allodynia behavior assessed with von Frey filaments in male or female rats that have undergone plantar incision surgery. Responses are shown at the following time points: baseline (before surgery), prior to treatment at 1 day after surgery, and at 1, 2, 4, and 6 hours after treatment at 1 day after surgery. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or morphine (6 mg/kg, delivered SC). There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant increases in withdrawal thresholds relative to vehicle in males at 1 hour post-treatment with 10, 30, and 60 mg/kg pregabalin (p<0.0001, 0.001, 0.0001, respectively) and morphine (p<0.0001); at 2 hours post-treatment with 10, 30, and 60 mg/kg pregabalin (p<0.001, 0.0001, 0.0001, respectively) and morphine (p<0.0001); at 4 hours post-treatment with 10, 30, and 60 mg/kg pregabalin (p<0.01, 0.001, 0.0001, respectively) and morphine (p<0.0001); and at 6 hours post-treatment with 10, 30, and 60 mg/kg pregabalin (p<0.0001, 0.01, 0.0001, respectively) and morphine (p<0.001). Dunnett’s tests found significant differences increases in withdrawal thresholds relative to vehicle in females at 1 hour post-treatment with 10, 30, and 60 mg/kg pregabalin (p<0.01, 0.05, 0.01, respectively) and morphine (p<0.0001); at 2 hours post-treatment with 30 and 60 mg/kg pregabalin (p<0.01, 0.001, respectively) and morphine (p<0.01); and at 4 hours post-treatment with 30 and 60 mg/kg pregabalin (p<0.05 for both comparisons).

Model: Plantar Incision Model in Rat (Brennan Model)

Animals were balanced across treatment groups based on body weight and post-surgery guarding scores.

Animals with ipsilateral post-surgery guarding scores ≥10 were included in the study.

Endpoint: Guarding Behavior

Two graphs show ipsilateral hind paw guarding behavior evaluated in male or female rats that have undergone plantar incision surgery. Responses are shown at the following time points: baseline (before surgery), prior to treatment at 1 day after surgery, and at 1, 2, 4, and 6 hours after treatment at 1 day after surgery. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or morphine (6 mg/kg, delivered SC). There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant decreases in guarding scores relative to vehicle in males at 1 hour post-treatment with 30 mg/kg pregabalin (p<0.05), 60 mg/kg pregabalin (p<0.01), and morphine (p<0.0001); at 2 hours post-treatment with 30 mg/kg pregabalin (p<0.001), 60 mg/kg pregabalin (p<0.001), and morphine (p<0.0001); at 4 hours post-treatment with 30 mg/kg pregabalin (p<0.001) and 60 mg/kg pregabalin (p<0.0001); and at 6 hours post-treatment with 30 mg/kg pregabalin (p<0.01) and 60 mg/kg pregabalin (p<0.01). Dunnett’s tests found significant decreases in guarding scores relative to vehicle in females at 1 hour post-treatment with 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.05), and morphine (p<0.0001); at 2 hours post-treatment with 30 mg/kg pregabalin (p<0.001), 60 mg/kg pregabalin (p<0.01), and morphine (p<0.0001); at 4 hours post-treatment with 30 mg/kg pregabalin (p<0.01) and 60 mg/kg pregabalin (p<0.01); and at 6 hours post-treatment with 30 mg/kg pregabalin (p<0.001) and 60 mg/kg pregabalin (p<0.05).

Model: L5/L6 Spinal Nerve Ligation Model

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Model: L5/L6 Spinal Nerve Ligation Model

Animals were balanced across treatment groups based on body weight and post-surgery positive responses to acetone trials.

Animals with ipsilateral post-surgery number of positive responses to acetone trials ≥2 were included in the study.

Endpoint: Rat Hind Paw Cold Allodynia (Acetone Evaporation) Test

Two graphs show ipsilateral hind paw cold allodynia behavior assessed with 5 trials of the acetone evaporation test in male or female rats that have undergone L5/L6 spinal nerve ligation surgery. Responses are shown at the following time points: baseline (before surgery), prior to treatment at 3 weeks after surgery, and at 1 and 3 hours after treatment at 3 weeks after surgery. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or the positive control morphine (6 mg/kg, delivered SC). There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant decreases in acetone responses relative to vehicle in males at 1 hour post-treatment with morphine (p<0.05) and at 3 hours post-treatment with 10 mg/kg pregabalin (p<0.0001). Dunnett’s tests found significant decreases in acetone responses relative to vehicle in females at 1 hour post-treatment with 60 mg/kg pregabalin (p<0.01) and morphine (p<0.001).

Method: Monosodium Iodoacetate (MIA) Model

Animals were balanced across treatment groups based on body weight and post-induction withdrawal thresholds.

Animals with ipsilateral pre-induction withdrawal responses >8.0g and post-induction withdrawal thresholds ≤4.0g were included in the study.

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Method: Monosodium Iodoacetate (MIA) Model

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Method: Monosodium Iodoacetate (MIA) Model

Animals were balanced across treatment groups based on body weight and post-induction weight bearing.

Animals with ipsilateral post-induction weight bearing of 10-40% of total hind paw weight bearing were included in the study.

Endpoint: Dynamic Weight Bearing Measurement Method

Two graphs show ipsilateral hind paw dynamic weight bearing behavior in male or female rats that have undergone injection of monosodium iodoacetate (MIA, 3 mg/50 µL) in the left hind limb knee joint. Responses are shown at the following time points: baseline (before MIA injection), Day 4 after MIA injection, and at 1 hour after treatment on Day 5. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or the positive control morphine (6 mg/kg, delivered SC). There were 8-9 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant increases in hind paw dynamic weight bearing relative to vehicle in males at 1 hour post-treatment with morphine (p<0.05). Dunnett’s tests found significant increases in hind paw dynamic weight bearing relative to vehicle in females at 1 hour post-treatment with morphine (p<0.05).

Method: Monosodium Iodoacetate (MIA) Model

Endpoint: Dynamic Weight Bearing Measurement Method

Model: Paclitaxel Chemotherapy-Induced Peripheral Neuropathy (CIPN) Model

Animals were balanced across treatment groups based on body weight and post-paclitaxel withdrawal thresholds.

Animals with average baseline withdrawal thresholds ≥8.0g and average post-paclitaxel withdrawal thresholds ≤4.0g were included in the study.

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Two graphs show hind paw mechanical allodynia behavior assessed with von Frey filaments in male or female rats that have undergone paclitaxel administration to model chemotherapy-induced peripheral neuropathy. Responses are shown at the following time points: baseline (before paclitaxel administration), prior to treatment at 6 weeks after the start of paclitaxel administration, and at 1, 2, 4, and 6 hours after treatment at 6 weeks after paclitaxel administration. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or the positive control morphine (6 mg/kg, delivered SC). Data are represented as the lowest response threshold (left or right hind paw) for each rat. There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant increases in withdrawal thresholds relative to vehicle in males at 1 hour post-treatment with 30 mg/kg pregabalin (p<0.05) and morphine (p<0.0001); at 2 hours post-treatment with 30 mg/kg pregabalin (p<0.001), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.01); at 4 hours post-treatment with pregabalin (p<0.01); and at 6 hours post-treatment with 30 mg/kg pregabalin (p<0.05). Dunnett’s tests found significant increases in withdrawal thresholds relative to vehicle in females at 1 hour post-treatment with 10 mg/kg pregabalin (p<0.05), 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.05), and morphine (p<0.0001); at 2 hours post-treatment with 30 mg/kg pregabalin (p<0.05), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.0001); and at 4 hours post-treatment with 60 mg/kg pregabalin (p<0.01).

Model: Paclitaxel Chemotherapy-Induced Peripheral Neuropathy (CIPN) Model

Animals were balanced across treatment groups based on body weight and post-paclitaxel positive responses to acetone trials.

Animals with baseline number of positive responses to acetone trials ≤2 and post-paclitaxel number of positive responses to acetone trials ≥3 were included in the study.

Endpoint: Rat Hind Paw Cold Allodynia (Acetone Evaporation) Test

Two graphs show hind paw cold allodynia behavior assessed with 10 trials of the acetone evaporation test (5 per hind paw) in male or female rats that have undergone paclitaxel administration to model chemotherapy-induced peripheral neuropathy. Responses are shown at the following time points: baseline (before paclitaxel), prior to treatment at 5 weeks after the first paclitaxel administration, and at 1 and 3 hours after treatment at 5 weeks after paclitaxel. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or the positive control morphine (6 mg/kg, delivered SC). There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant decreases in acetone responses relative to vehicle in males at 1 hour post-treatment with 10 mg/kg pregabalin (p<0.01), 30 mg/kg pregabalin (p<0.0001), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.0001) and at 3 hours post-treatment with 30 mg/kg pregabalin (p<0.001), 60 mg/kg pregabalin (p<0.001), and morphine (p<0.0001). Dunnett’s tests found significant decreases in acetone responses relative to vehicle in females at 1 hour post-treatment with 10 mg/kg pregabalin (p<0.0001), 30 mg/kg pregabalin (p<0.0001), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.0001) and at 3 hours post-treatment with 10 mg/kg pregabalin (p<0.0001), 30 mg/kg pregabalin (p<0.0001), and 60 mg/kg pregabalin (p<0.0001).

Model: Oxaliplatin Chemotherapy-Induced Peripheral Neuropathy (CIPN) Model

Animals were balanced across treatment groups based on body weight and post-oxaliplatin withdrawal thresholds.

Animals with average baseline withdrawal thresholds ≥8.0g and post-oxaliplatin withdrawal thresholds ≤4.0g were included in the study.

Endpoint: Rat Hind Paw Mechanical Allodynia Behavior (von Frey Filaments) Method

Two graphs show hind paw mechanical allodynia behavior assessed with von Frey filaments in male or female rats that have undergone oxaliplatin administration to model chemotherapy-induced peripheral neuropathy. Responses are shown at the following time points: baseline (before oxaliplatin administration), prior to treatment at 7 weeks after the start of oxaliplatin administration, and at 1, 2, 4, and 6 hours after treatment at 7 weeks after oxaliplatin administration. The treatments are vehicle (saline, delivered PO), pregabalin (10, 30, or 60 mg/kg, delivered PO), or the positive control morphine (6 mg/kg, delivered SC). Data are represented as the lowest response threshold (left or right hind paw) for each rat. There were 10 rats per group. A significant interaction of time x treatment was found in a two-way repeated measures ANOVA for each sex. Dunnett’s tests found significant increases in withdrawal thresholds relative to vehicle in males at 1 hour post-treatment with 10 mg/kg pregabalin (p<0.05), 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.01), and morphine (p<0.0001); at 2 hours post-treatment with 10 mg/kg pregabalin (p<0.001), 30 mg/kg pregabalin (p<0.001), 60 mg/kg pregabalin (p<0.001), and morphine (p<0.0001); at 4 hours post-treatment with 60 mg/kg pregabalin (p<0.01); and at 6 hours post-treatment (p<0.01). Dunnett’s tests found significant increases in withdrawal thresholds relative to vehicle in females at 1 hour post-treatment with 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.001), and morphine (p<0.0001); at 2 hours post-treatment with 10 mg/kg pregabalin (p<0.001), 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.001); at 4 hours post-treatment with 10 mg/kg pregabalin (p<0.0001), 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.01), and morphine (p<0.001); and at 6 hours post-treatment with 10 mg/kg pregabalin (p<0.001), 30 mg/kg pregabalin (p<0.01), 60 mg/kg pregabalin (p<0.0001), and morphine (p<0.05).

Model: Oxaliplatin Chemotherapy-Induced Peripheral Neuropathy (CIPN) Model

Animals were balanced across treatment groups based on body weight and post-oxaliplatin positive responses to acetone trials.

Animals with baseline number of positive responses to acetone trials ≤2 and post-oxaliplatin number of positive responses to acetone trials ≥3 were included in the study.

Endpoint: Rat Hind Paw Cold Allodynia (Acetone Evaporation) Test

Method: Conditioned place preference

Animals were balanced across treatment groups such that Day 1 preference values were equivalent with averages all close to the chance level.

Animals with a strong bias to one compartment (>75%) on Day 1 were removed during the rebalance procedure.

Two graphs show percent of time spent in the treatment-paired chamber on Day 10 after conditioning with vehicle (saline, IP), pregabalin (3, 10, 30, or 100 mg/kg, IP), or oxycodone (3 mg/kg, IP) in male and female rats (n=13-16 rats/group). During conditioning, rats were placed in the chambers immediately after treatment with vehicle, pregabalin, or oxycodone. A significant effect was found in a one-way ANOVA for males. Dunnett’s tests found significant increases in the percent of time spent in the treatment-paired chamber when rats were treated with oxycodone relative to rats treated with vehicle in males (p<0.01). Data were analyzed with GraphPad Prism.

Method: Conditioned place preference

Two graphs show the change in preference scores (calculated as the difference in time spent in the treatment-paired chamber from Day 1 to Day 10) after treatment and conditioning with vehicle (saline, IP), pregabalin (3, 10, 30, or 100 mg/kg, IP), or oxycodone (3 mg/kg, IP) in male and female rats (n=14-16 rats/group). During conditioning, rats were placed in the chambers immediately after treatment with vehicle, pregabalin, or oxycodone. A significant effect was found in a one-way ANOVA for each sex. Dunnett’s tests found significant increases in the preference score when rats were treated with oxycodone relative to rats treated with vehicle in males (p<0.05) and females (p<0.05). Data were analyzed with GraphPad Prism.

Method: Intravenous self-administration

Within each group on each day, data points that exceeded ± two standard deviations from the mean were removed from the analysis.

Two graphs show the number of infusions delivered in a fixed ratio of 3 lever presses for 1 intravenous infusion of vehicle (saline), pregabalin (0.1, 0.3, 1, or 3 mg/kg/infusion), or oxycodone (0.06 mg/kg/infusion) after food training in male and female rats (n=10-13/group). Dunnett’s tests were performed after finding a significant interaction of time x treatment in a mixed effects analysis performed on the data for Days 5-20 for each sex. The number of infusions of oxycodone was significantly higher than the number of infusions of vehicle on each day for Days 9-20 for males and Days 5-20 for females. Data were analyzed with GraphPad Prism.

This work was conducted by PsychoGenics Inc. (Paramus, NJ) in collaboration with PSPP, NINDS, NIH under contract # 75N95019D00026. Prescribing information for clinically used controls can be found at labels.fda.gov. Information for icons representing experimental design details can be found through the NINDS Office of Research Quality https://go.nih.gov/Yw2tHGI.

PREGABALIN

Formulation

Results

Protein Binding

Pharmacokinetics: Concentration in Plasma and Brain

Pharmacokinetics: Calculated Parameters

Irwin: Total Observations

Irwin: Behavioral Severity Scores

Irwin: Body Temperature

Rotarod

Plantar Incision: von Frey

Plantar Incision: Guarding Behavior

L5/L6 Spinal Nerve Ligation: von Frey

L5/L6 Spinal Nerve Ligation: Acetone

Monosodium Iodoacetate (MIA): von Frey (Single Administration)

Monosodium Iodoacetate (MIA): von Frey (Repeated Administration)

Monosodium Iodoacetate (MIA): Dynamic Weight Bearing (Single Administration)

Monosodium Iodoacetate (MIA): Dynamic Weight Bearing (Repeated Administration)

Paclitaxel Chemotherapy-Induced Peripheral Neuropathy: von Frey

Paclitaxel Chemotherapy-Induced Peripheral Neuropathy: Acetone

Oxaliplatin Chemotherapy-Induced Peripheral Neuropathy: von Frey

Oxaliplatin Chemotherapy-Induced Peripheral Neuropathy: Acetone

Conditioned Place Preference: Bias Test

Conditioned Place Preference: Preference Score

Intravenous Self-Administration: Acquisition Training