Animal Models of Musculoskeletal Pain Kathleen A. Sluka, PT, PhD Associate Professor Physical Therapy and Rehabilitation Science Graduate Program Neuroscience Graduate Program Pain Research Program University of Iowa Iowa City, IA 52242

Goals • Animal models of musculoskeletal pain – Pain-like behaviors – Neuronal changes

• Animal models of back pain – Pain-like behaviors – Neuronal changes – Potential mediators

Pain Generators in Low Back • • • • •

Muscle Facet Joint Ligaments Intervertebral disc Nerve root

Animal Models of Musculoskeletal Pain • Inflammatory (Mense-muscle, Schaible and Schmidtjoint)

– Injection of carrageenan and/or kaolin – Produces acute and chronic inflammation – Produces mechanical and heat hyepralgesia for 8 weeks

• Non-inflammatory (Sluka-muscle) – Two injections of acid into the muscle – No peripheral tissue damage – Produced mechanical hyperaglesia for up to 4 weeks

Models

Saline/ Carrageenan

Mechanical and heat stimuli Sluka et al., Muscle and Nerve, 24: 37-46 2001; Radhakrishnan et al., Pain, 104: 567-577 2003

Von Frey filament Pain Research Program

UNIVERSITY of IOWA

Acidic Saline Model • • • •

No heat hyperalgesia (Sluka et al., 2001) No motor deficits (Sluka et al., 2001) Minimal to no tissue damage (Sluka et al., 2001) pH decreases to a maximum of 6.0 (with 4.0) (Sluka et al., 2001)

• Ipsilateral lidocaine or unilateral dorsal rhizotomy has no effect on the contralateral hyperalgesia (Sluka et al., 2001) • Hyperalgesia reduced by intrathecal opioids, NMDA and AMPA/KA antagonists (Sluka et al., 2002, JPET 302: 1146-1150; Skyba et al., Pain, 98: 69-78, 2002) Pain Research Program UNIVERSITY of IOWA

Animal Models of Low Back Pain • Does injury to the disc produce pain? • Does disc degeneration produce pain? • Does herniation of the disc produce pain?

Neuronal changes after deep tissue injury • Sensitization of peripheral nerves – Increased response to movement – Increased spontaneous acvitity

• Sensitization of central neurons – Increased response to joint movement – Increased response to cutaneous stimulation – Increased size of receptive field

• References: Schaible and Schmidt, J Neruophysiol 54: 1109-1122, 1985; Schaibel and Schmidt, J Neurophysiol 60: 2180-2195, 1988; Hoheisel et al. Neurosci Lett 1993;153:9-12; Neugebauer et al. J Neuroscience 1993;70:1365-1377; Sluka et al., Pain, 2003; 106: 229239; Ma and Sluka, Exp Br Res 137:94-102, 2001

Innervation of Intervertebral Disc 100

Innervation of intervertebral discs

Percent

80 Control non-pain level pain-level

60

PGP 9.5

40 20

Substance P

0 Outer

Middle Inner Annulus Fibrosis

N. Pulposis

Freemont et al., 1997, Lancet 350: 178-181 140

Synaptophysin

Distribution of Neurons in DRG from L5/L6 disc

Total Number (n=16)

120 100 80 60 40 20 0 T12 T13

L1

L2

L3

L4

L5

L6

Vertebral Level

Aoki et al., The Spine Journal 4: 275-280, 2004

Palmgren et al., 1997; Spine 24: 2075-1079

Innervation Patterns for Back see Aoki et al., Life Sciences 74: 2627-2642 Innervation of: L5-L6 IVD: L5-L6 facet: Muscle L5 level: Skin L5 level: SI Joint:

T13-L6 L1-L5 L1-L6 L1-L2 L3-S3

Summary – Innervated by DRG from multiple segments – Increased innervation in painful discs and innervation of new areas – Injury to disc causes mechanical hyperaglesia – Nucleus Pulposis applied to nerve causes mechanical hyperalgesia – Nucleus Pulposis + Compression increases hyperalgesia – Injury to nerve causes hyperalgesia

References • Ohtori et al., J Pain, 5:385-391 • Kawakami et al., in Press • Kawakami et al., J Orthop Res. 2003 May;21(3):535-9. • Onda et al., 2005, Spine 30: 188-193 • DeLeo JA

Pathomechanism of radicular pain chemicals

cytokines cytokines

epidural space inflammation

PLA PLA 22 NO NO etc

nucleus pulposus nerve root DRG

axon axon

CNS

anulus anulus fibrosus fibrosus hyperalgesia, hyperalgesia, pain pain

Kawakami

Inflammatory Cytokines • Herniated discs release inflammatory cytokines: IL-1β, IL-6, TNF, prostaglandins – Ahn et al., Spine 2002, 27: 911-917 – ODonnell and ODonnell Spine, 1996: 1653-1655 – Kang et al., Spine, 1996: 21: 271-277

• Increase mechanical sensitivity of the receptive field by IL-1β and TNF after application to sacral roots – Ozaktay et al. Europ Spine J 2002, 11: 467-475

• Blockade of TNF reduces low back pain in humans – Tobinick et al., Swiss Medical Weekly, 2003, 133: 170-177 – Genevay et al. Ann Rheum Dis, 2004, 63: 1120-1123 – Korhonen et al., Spine, 2004, 29: 2115-2119

Summary • Low back pain – Inflammatory component – Cytokines and prostaglandins likely are key factors that result in local and radicular pain

• Future studies aimed at deciphering mechanisms that produce low back pain, and distinguish this from radicular pain

Acknowledgements • Sluka Laboratory – Rajan Radhakrishnan, Marie Hoeger Bement, Anshu Kalra, David Skyba, Katherine Audette, Ellen King, Tammy Lisi, Jennifer Rohwling, Sarah Eikenberry, Jason Wilkins, Becky Spitznagle

• Collaborators – Steven Moore, Michael Welsh, Sergio Mendoza, Jeff Stevens

• Others – Dr. Joyce DeLeo, PhD, Department of Pharmacology and Toxicology, Department of Anesthsia, Dartmouth Medical School, New Hampshire – Dr. Kawamati MD, PhD, Department of Orthopaedic Surgery, Wakayama Medical University, Japan

• Funded by – National Institutes of Health, Medtronics, Carver College of Medicine University of Iowa