Treatment of neuropathic pain is a major clinical problem. This study shows expression of phospholipase ß3 (PLCß3) in mouse and human DRG neurons, mainly in small ones and mostly with a nonpeptidergic phenotype. After spared nerve injury, the pain threshold was strongly reduced, and systemic treatment of such animals with the unselective PLC inhibitor U73122 caused a rapid and long-lasting (48-h) increase in pain threshold. Thus, inhibition of PLC may provide a way to treat neuropathic pain.galanin receptor 2 ͉ nerve injury ͉ neuropeptide ͉ pain treatment ͉ sensory neuron T he phospholipase C (PLC) family consists of several isoforms, such as PLC, ␥, ␦, and , which are linked to membrane receptors mediating intracellular signaling cascades (1-3). PLC has been demonstrated in dorsal root ganglion (DRG) neurons (4-6). Of the 4 major PLC isoforms, PLC1, -3, and -4 expressed in DRGs, the PLC3 transcript shows the clearly highest levels (5).Involvement of PLC3 in regulation of pain and related sensations at the spinal level has been demonstrated in several studies. For example, PLC3 Ϫ/Ϫ mice show enhanced morphine responsiveness (7) and have a deficient scratching (''itching'') behavior (5). Bradykinin-and nerve growth factor-induced hypersensitivity involves PLC3 activation (8), and PLC3 is important for PKC 2 -mediated acute and chronic inflammatory pain (6). Other isoforms of PLC have also been associated with pain. Thus, there is evidence that PLC1 is involved in the thermal nociceptive response (10), and PLC4 Ϫ/Ϫ mice show attenuated nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation (11). Moreover, inhibition of PLC has been shown to attenuate acute and chronic inflammatory hyperalgesia (9).In the present study, we have monitored pain thresholds and the effect of an unselective PLC inhibitor (U73122) in the spared nerve injury (SNI) model of neuropathic pain in mouse (12, 13). In parallel we have analyzed the localization of PLCß3 and a number of transmitter related markers in DRGs and spinal cord and the effect of SNI. Human DRGs were also studied.Results SNI-Induced Hyperalgesia. After SNI, mice developed mechanical allodynia-like behavior as shown by the decrease in withdrawal threshold of the hindpaw ipsilateral to the nerve injury. This was seen 2 days after the surgery, with a pronounced effect between 7 and 21 days (Fig. 1A). A decrease, albeit less pronounced, was also seen in the contralateral hindpaw between day 7 and 21 after nerve injury (Fig. 1A).
