title: Evaluating the effects of recombinant human bone morphogenetic protein-2 on pain-associated behaviors in a rat model following implantation near the sciatic nerve.
abstract: OBJECTIVE It has been hypothesized that the recombinant human bone morphogenetic protein-2 (rhBMP-2) amplification of the host inflammatory response interacts with nerves in the spine and contributes to the occurrence of new, postoperative complaints of radiculitis. This in vivo rat study was conducted to assess the capacity for rhBMP-2/ACS (rhBMP-2 applied to absorbable collagen sponge [ACS]) to stimulate pain-associated behaviors in the rat chronic constriction injury (CCI) model. METHODS Rats were randomly assigned to one of 14 treatment groups. Half of the animals underwent a sham procedure in which the left sciatic nerve was exposed and manipulated but no ligature was placed (Sham cohort), while the remaining animals had chromic gut sutures tied around the sciatic nerve to induce CCI (CCI cohort). The following test articles were applied to the sciatic nerve in each cohort: saline alone, saline applied to ACS, 0.1 mg/ml rhBMP-2 applied to ACS, or 1.0 mg/ml rhBMP-2 applied to ACS. The ACS was either wrapped around the sciatic nerve or implanted adjacent to the nerve. Thermal withdrawal latency was assessed on Days 7, 14, 21, and 28 postoperatively. Isolated nerves from selected rats in each group were examined and assessed for histopathological changes on Days 3, 7, 14, and 28. RESULTS CCI produced a significant pain behavioral response for all treatment groups at all time points. In the Sham cohort, 0.1 mg/ml rhBMP-2/ACS wrapped around the nerve (WRP) decreased thermal withdrawal on Day 28, and 1.0 mg/ml rhBMP-2/ACS placed adjacent to the nerve (ADJ) decreased thermal withdrawal on Days 21 and 28. Conversely, in the CCI cohort, 0.1 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; 1.0 mg/ml rhBMP-2/ACS ADJ increased thermal withdrawal latencies on Day 7; and 1.0 mg/ml rhBMP-2/ACS WRP increased thermal withdrawal on Days 7 and 14. Histologically, the effect of rhBMP-2 on nerve inflammation was unclear, as inflammatory cell infiltration was similar in the rhBMP-2/ACS and saline/ACS groups. rhBMP-2 was variably associated with bone formation within the epineurium at 14 days, and more prevalently at 28 days, with no clear relationship between dose or ACS positioning. CONCLUSIONS In this study, rhBMP-2/ACS did not appear to induce pain independent of grossly visible ectopic bone formation. At the earliest time points, rhBMP-2 appeared to have a neuroprotective effect as evidenced by decreased pain exhibited by the rhBMP-2-treated animals in the CCI cohort, but this effect diminished over time, and by Day 28, the pain behavioral responses in the rhBMP-2-treated group were comparable to those in the group in which saline was applied to the nerve. In the Sham cohort, there was a dose-independent induction of pain at later time points, presumably due to new bone formation mechanically irritating the nerve. Histological examination revealed nerve lesions that appeared to be caused by mechanical trauma associated with surgical manipulation of the nerve during placement of the ACS and/or CCI sutures.
authors.affiliation: Spinal and Biologics Division, Medtronic, Memphis, Tennessee;
authors.forename: John M
authors.initials: JM
authors.lastname: Zanella
authors.affiliation: Behavioral Neuropharmacology Laboratory Biosciences Division, SRI International, Menlo Park, California; and.
authors.forename: Nahid
authors.initials: N
authors.lastname: Waleh
authors.affiliation: Behavioral Neuropharmacology Laboratory Biosciences Division, SRI International, Menlo Park, California; and.
authors.forename: Juan
authors.initials: J
authors.lastname: Orduña
authors.affiliation: Behavioral Neuropharmacology Laboratory Biosciences Division, SRI International, Menlo Park, California; and.
authors.forename: Jose
authors.initials: J
authors.lastname: Montenegro
authors.affiliation: Medtronic Physiological Research Laboratories, Minneapolis, Minnesota.
authors.forename: Jaime
authors.initials: J
authors.lastname: Paulin
authors.affiliation: Spinal and Biologics Division, Medtronic, Memphis, Tennessee;
authors.forename: William F
authors.initials: WF
authors.lastname: McKay
authors.affiliation: Spinal and Biologics Division, Medtronic, Memphis, Tennessee;
authors.forename: Jared
authors.initials: J
authors.lastname: Wilsey
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage* / Q000009:adverse effects; D002908:Chronic Disease; D003094:Collagen; D003251:Constriction, Pathologic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D004343:Drug Implants; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010146:Pain / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D010147:Pain Measurement; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D004343:Drug Implants; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D003094:Collagen
keywords: ACS = absorbable collagen sponge; ADJ = sponge placed adjacent to the nerve; BMP = bone morphogenetic protein; CCI = chronic constriction injury; H & E = hematoxylin and eosin; WRP = sponge wrapped around the nerve; bone morphogenetic protein-2; chronic constriction injury; inflammation; rat; rhBMP-2 = recombinant human BMP-2