Mechanisms of Spinal Manipulative Therapy for Neuropathic Pain

Neuropathic pain associated with chronic pain conditions and peripheral neuropathy exerts devastating personal and socioeconomic burdens. Pharmacological agents are the mainstay of symptoms management, however, pain relief is usually temporary and there can be major side effects. With opioids, there is an epidemic of addiction, abuse, and overdose. For these reasons, complementary and integrative health interventions, including spinal manipulative therapy (SMT), are being used individually or in multimodal and multidisciplinary chronic pain management approaches as non-pharmacologic and conservative treatments. The effectiveness of SMT and the neurobiological mechanisms by which it alleviates neuropathic pain are unclear. Identifying these mechanisms not only will advance the field by filling critical knowledge gaps but also will improve clinical efficacy when the results are translated. To begin to address these gaps, we generated preliminary data using low velocity variable amplitude spinal manipulation (LVVA-SM). Our LVVA-SM paradigm (10 min, 0.16Hz, 20° flexion, at the L5 vertebra) mimics a frequently utilized non-thrust SMT technique for the treatment of chronic low back pain without or with neuropathic leg pain. We found that LVVA-SM reduced hypersensitivity to a mechanical stimulus (von Frey monofilaments) applied to the plantar hindpaw in the rat spared nerve injury (SNI) model of neuropathic pain. Our long-term goal is to determine the neurobiological mechanisms underlying this anti-allodynic effect of LVVA-SM. This R15 application proposes to characterize LVVA-SM-induced anti-allodynia (Aim 1) and then leverage a multidisciplinary collaboration to determine whether this is mediated by endogenous activation of spinal cord cannabinoid receptors (Aim 2). The goals of the R15 program will be met by strengthening Palmer College of Chiropractic’s research mission. This will allow students to learn about biomedical research of SMT through mentored hands-on participation in all of the phases of the project, which is directly relevant to the profession’s objective of using evidence-based SMT to reduce chronic pain. Aim 1 will test the hypothesis that the cyclical passive flexion associated with LVVA-SM inhibits behavioral and spinal molecular signs of chronic neuropathic pain. LVVA-SM utilizes stabilization (S), traction (T), and cyclical passive flexion (CPF) of the vertebral column (VC). CPF involves continuous passive movement of joints which produces analgesia in both clinical and experimental chronic and acute pain. To test the hypothesis that CPF is required for the analgesic effect of LVVA-SM in SNI, we will evaluate the effect of continuous cyclical 0.16Hz passive 20° flexion for 10 min at the L5 vertebra on static hindpaw mechanical allodynia and activation of dorsal horn neurons in the lumbar spinal cord. To dissect CPF from the other components of LVVA-SM, rats will be assigned to the following groups: 1) No isoflurane anesthesia; 2) Anesthesia for 10 min; 3) Anesthesia plus VCS; 4) Anesthesia plus VCT; 5) Anesthesia plus VCS plus VCT; 6) Anesthesia plus CPF; 7) Anesthesia plus VCS plus CPF; 8) Anesthesia plus VCT plus CPF; or 9) Anesthesia plus LVVA-SM (VCS plus VCT plus CPF). Allodynia will be assessed with measurement of von Frey thresholds before and after each set of procedures. Neuron activation will be assessed with immunohistochemical quantification of non-noxious stimulus-evoked pERK-positive profiles in the dorsal horn. We predict that CPF will generate greater anti-allodynia and greater inhibition of neuron activation than VCS and/or VCT alone. Furthermore, we predict that the afferent input of CPF together with both VCS and VCT will produce the greatest effects. Aim 2 will test the hypothesis that endogenous activation of CB1 and CB2 receptors in the dorsal horn contributes to the anti-allodynic effect of LVVA-SM. The activity-dependent endocannabinoid neurotransmitter system and its cannabinoid receptors are involved in the anti-allodynic effect of ankle joint mobilization in a mouse model of post-operative pain. This provides the premise for our hypothesis that the endocannabinoid system contributes to the analgesic action of SMT. Cannabinoid receptors are expressed by dorsal horn neurons (CB1) and glia (CB2), cell types that modulate spinal nociceptive transmission. Both receptors are upregulated within the superficial laminae in rodent neuropathic pain models. For CB2, this occurs in activated glia and primary afferent terminals. Spinal cord levels of anandamide, a primary endogenous ligand, increase as well. Possibly synergistically or additively with receptors upregulation, inhibiting anandamide degradation by FAAH with URB937 also potentiated ankle joint mobilization’s anti-allodynic effect. To determine whether LVVA-SM recruits cannabinoid receptors in the dorsal horn for its anti-allodynia effects, we will 1) establish SNI-induced allodynia; 2) administer various doses of selective inverse agonists/antagonists at CB1 (AM281) or CB2 (AM630) receptors or administer URB937; 3) apply LVVA-SM or control treatments; and then 4) measure behavior and spinal pERK activation. We predict that CB1 and/or CB2 antagonism will prevent the ability of LVVA-SM to reduce allodynia and dorsal horn neuron (CB1,2) and glia (CB2) activation. We also predict that the anti-allodynic and spinal pERK effect of LVVA-SM will be potentiated by administering URB937.