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NEUROPHARMACOLOGY

Different Effects of Opioid and Cannabinoid Receptor Agonists on C-Fiber-Induced Extracellular Signal-Regulated Kinase Activation in Dorsal Horn Neurons in Normal and Spinal Nerve-Ligated Rats

Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Y.K., R.-R.J.); and Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (T.K.)

Nerve injury results in neuropathic pain, a debilitating pain condition. Whereas cannabinoids are consistently shown to attenuate neuropathic pain, the efficacy of opioids is highly controversial. Molecular mechanisms underlying analgesic effects of opioids and cannabinoids are not fully understood. We have shown that the signaling molecule ERK (extracellular signal-regulated kinase) is activated by C-fiber stimulation in dorsal horn neurons and contributes to pain sensitization. In this study, we examined whether opioids and cannabinoids can affect C-fiber-induced ERK phosphorylation (pERK) in dorsal horn neurons in spinal cord slices from normal and spinal nerve-ligated rats. In normal control spinal slices, capsaicin induced a drastic pERK expression in superficial dorsal horn neurons, which was suppressed by morphine (10 µM), the selective µ-opioid receptor agonist DAMGO [[D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (1 µM)], and the selective CB1 receptor ACEA agonist [arachidonyl-2'-chloroethylamide (5 µM)]. One week after spinal nerve ligation when neuropathic pain is fully developed, capsaicin induced less pERK expression in the injured L₅-spinal segment. This pERK induction was not suppressed by morphine (10 µM) and DAMGO (1 µM) but was enhanced by high concentration of DAMGO (5 µM). In contrast, ACEA (10 µM) was still very effective in inhibiting capsaicin-induced pERK expression. In the adjacent L₄ spinal segment, both DAMGO and ACEA significantly suppressed pERK induction by capsaicin. These results indicate that, after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L₅ but not in the intact L₄ spinal segment, whereas cannabinoids still maintain their efficacy.

Address correspondence to: Dr. Ru-Rong Ji, Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Medical Research Building, Room 604, Boston, MA 02115. E-mail: rrji{at}zeus.bwh.harvard.edu