Despite the considerable advancements in our understanding of the mechanisms of acute and chronic pain, inadequate pain relief remains a major issue in chronic pain. Cannabinoid agonists acting on cannabinoid receptors (CBR) 1 and 2 have shown great promise in both animal and human studies as analgesics, without a clear understanding of the mechanism of action. CBR1 agonists produce undesirable neurological effects which limit their clinical use. We have shown that CBR2 are exclusively expressed in microglia in spinal cord following L5 nerve transection and that a selective CBR2 agonist induces anti-allodynic effects and reduces microglial reactivity in postoperative and neuropathic pain models without inducing neurological side effects. This strongly suggests a direct action on glial cells. In order to develop effective analgesic drug strategies, pathophysiological mechanisms for chronic pain and mechanisms of potential new analgesic drugs need to be elucidated. The primary purpose of this proposal is to address a novel CBR2 mechanism of action in microglia and to identify and describe a novel specific microglial molecular signaling pathway related to pain information processing. We have previously suggested that microglia playa key role in initiating and maintaining persistent pain states by producing proinflammatory factors such as cy1okines/chemokines. It has been shown that microglial extracellular signal-regulated kinase-1/2 (ERK-1/2) is increased following peripheral nerve injury, and its blockade reverses peripheral nerve injury-induced allodynia. The inhibition of pERK-1/2 results in a reduction of algesic factors, such as cy1okines, nitric oxide (NO) or prostaglandins. Thus far, the mechanisms involved in nerve injury-induced pERK-1/2 are unknown. Phosphatases are regulators of mitogen-activated protein kinases (MAPKs). MAPK phosphatase (MKP)-1 modulates various MAPKs, including pERK-1I2. MKP- 3 is a specific regulator of pERK-1I2. Our preliminary data suggest that JWH015, a CBR2 agonist, reduces pERK by means of MKP-1/3 induction in primary microglial cultures. In vivo, we have observed that L5 nerve transection reduces MKP-1, which is restored by i.t. administration of JWH015 in association with its antiallodynic effects. Based on these observations we propose to investigate the following hypothesis: Spinal CBR2 activation induces MKP-1 and MKP-3 that leads to ERK-112 dephosphorylation and a decrease in algesic mediators, which in turn induces anti-al/odynic effects in neuropathic pain. The central hypothesis will be tested by using established methods in our laboratory to investigate the following revised Specific Aims designed to be completed in two years: (1) Evaluate whether spinal CBR2 activation induces anti-allodynic effects by inhibiting microglial ERK phosphorylation via MKP-1/3 induction after peripheral nerve injury in rats, and (2) Establish the in vitro role of ERK phosphorylation and MKP-1/3 expression on algesic mediators and CBR2 activation in LPS-activated microglia. The development of new drug strategies to treat acute and chronic pain safely and effectively will result in an invaluable improvement for millions of patients.

Public Health Relevance

Chronic neuropathic pain remains a serious and debilitating syndrome without adequate treatments. This research will study how specific cannabinoid drugs work to decrease painful neuropathy and improve the quality of life without adverse side effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Purohit, Vishnudutt
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Dartmouth College
Schools of Medicine
United States
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Jacobs, Valerie L; De Leo, Joyce A (2013) Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model. J Neurooncol 114:33-42
Landry, Russell P; Martinez, Elena; DeLeo, Joyce A et al. (2012) Spinal cannabinoid receptor type 2 agonist reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatases in a rat model of neuropathic pain. J Pain 13:836-48
Ndong, Christian; Landry, Russell P; DeLeo, Joyce A et al. (2012) Mitogen activated protein kinase phosphatase-1 prevents the development of tactile sensitivity in a rodent model of neuropathic pain. Mol Pain 8:34
Jacobs, Valerie L; Landry, Russell P; Liu, Yingna et al. (2012) Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro Oncol 14:119-31
Jacobs, Valerie L; Liu, Yingna; De Leo, Joyce A (2012) Propentofylline targets TROY, a novel microglial signaling pathway. PLoS One 7:e37955
Jacobs, Valerie L; Valdes, Pablo A; Hickey, William F et al. (2011) Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro 3:e00063
Alkaitis, Matthew S; Solorzano, Carlos; Landry, Russell P et al. (2010) Evidence for a role of endocannabinoids, astrocytes and p38 phosphorylation in the resolution of postoperative pain. PLoS One 5:e10891