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Noxious Thermal and Chemical Stimulation Induce Increases in 3H The Journal of Neuroscience, May 1995, /5(5): 3263-3272 Noxious Thermal and Chemical Stimulation Induce Increases in 3H-Phorbol 12,13=Dibutyrate Binding in Spinal Cord Dorsal Horn as Well as Persistent Pain and Hyperalgesia, Which Is Reduced by Inhibition of Protein Kinase C Kiran Yashpal,‘,” Graham M. Pitcher,’ Angele Parent,2,4 RBmi Quirion,2,4 and Terence J. Coderre1.3.5 ‘Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, Departments of *Psychiatry and 3Psychology, McGill University, Montreal, 4Douglas Hospital Research Center, Vet-dun, and 5Centre de recherche en sciences neurologiques et Dkpat-tement de mkdecine, Universit6 de Montreal, Canada We have previously suggested that protein kinase C (PKC) ry, forma/in test, protein kinase C, phorbol ester, 3H-phor- contributes to persistent pain in the formalin test. This bol-12,lSdibutyrate binding, protein kinase C inhibitors, study compared the effects of pharmacological inhibition neuronal plasticity] of PKC with either GF 109203X or chelerythrine on persis- tent pain following noxious chemical stimulation with its Recent evidence suggests that following peripheral tissue injury effects on mechanical hyperalgesia, which develops in the or intense noxious stimulation there are specific changes in cen- hindpaw contralateral to an injury produced by noxious tral neuronal excitability that contribute to persistent pain and thermal stimulation. Furthermore, we have assessed hyperalgesia (Woolf, 199 I ; Coderre et al., 1993). Furthermore, changes in membrane-associated PKC in spinal cord in re- there is evidence that this injury or noxious stimulus-induced sponse to both noxious chemical and thermal stimulation. hyperexcitability is influenced by activity at excitatory amino Nociceptive responses, to a hindpaw injection of 50 PI of acid (EAA) and substance P/neurokinin- 1 (NK- 1) receptors. Re- 2.5% formalin, and flexion reflex thresholds, to mechanical petitive C-fiber afferent nerve stimulation leads to a cumulative- stimulation (Randall-Selitto test) in the hindpaw contralat- ly increasing postsynaptic depolarization or wind-up of dorsal eral to a thermal injury (15 set immersion in water at 55”(Z), horn neurons that is blocked by N-methyl-D-aspartate (NMDA) were assessed following intrathecal injection of PKC inhib- receptor antagonists (Davies and Lodge, 1987; Dickenson and itors (GF 109203X or chelerythrine). Changes in the levels Sullivan, l987), while injury or intense afferent nerve stimula- of membrane-associated PKC, as assayed by quantitative tion produces a slow prolonged excitatory postsynaptic potential autoradiography of the specific binding of 3H-phorbol- that is blocked by NK-I receptor antagonists (De Koninck and 12,13-dibutyrate (3H-PDBu) in spinal cord sections, were Henry, 1991). Tissue injury produces an expansion of the re- assessed in rats after noxious chemical (50 PI of 5.0% for- ceptive fields of neurons responding to inputs from areas adja- malin) and noxious thermal (90 set immersion in water at cent to the area of injury that is blocked by NMDA antagonists 55°C) stimulation. Inhibitors of PKC (GF 109203X, chelery- (Dubner and Ruda, 1992). Injury of a rat’s limb also produces thrine), produced significant reductions of nociceptive re- a spinally mediated increase in the excitability of ipsilateral and sponses to 2.5% formalin, as well as a significant reduction contralateral flexion reflexes that is blocked by both NK-1 and in the mechanical hyperalgesia in the hindpaw contralat- NMDA receptor antagonists (Coderre and Melzack, 199 1; Woolf eral to a thermal injury. In addition, both noxious chemical and Thompson, 1991). and thermal stimulation produced significant increases in It has been shown that synaptic activation of NMDA and specific 3H-PDBu binding in the dorsal horn of the lumbar NK-1 receptors produces brief effects lasting, at most, millisec- spinal cord, likely reflecting alterations in membrane-as- onds to seconds for NMDA receptors (Gerber et al., 1991) and sociated PKC. The results provide both pharmacological seconds to minutes for NK-I receptors (Urban and Randic, and anatomical evidence that persistent pain produced by 1984; De Koninck and Henry, 1991.). Thus, it is unlikely that chemical stimulation with formalin and mechanical hyper- NMDA or NK-I receptor activation by themselves can account algesia in the hindpaw contralateral to a thermal injury are for the prolonged changes in neuronal excitability that follows influenced by the translocation and activation of PKC in peripheral tissue injury. It is possible, however, that these pro- spinal cord dorsal horn neurons. longed changes in excitability depend on the ability of EAA and [Key words:pain, nociception, hyperalgesia, tissue inju- NK-I receptors to stimulate the production or activation of var- ious intracellular messengers. Both EAA and NK-I receptor ac- tivation triggers the production of various intracellular second Received July IS, 1994; revised Oct. 27, 1994; accepted Dec. 2, 1994. messengers in neuronal cells. Activity at metabotropic EAA We thank Dr. J. G. Chabot for his time and help with the image analysis system. We also thank Dr. J. L. Henry for reviewing the manuscript. This work (Sladeczek et al., 1985; Sugiyama et al., 1987) or NK-1 (Watson was supported by grants from MRC and FRSQ to T.J.C. and MRC to R.Q. and Downes, 1983) receptors stimulates the hydrolysis of phos- Correspondence should he addressed to Terence J. Coderre, Ph.D., Director, Pain Mechanisms Laboratory, Clinical Research Inatittlte of Montreal, Quebec, phatidyinositol (PI) leading to an increased production of the Canada, H2W lR7. intracellular messengers inositol trisphosphate (IP,) and diacyl- Copynght 0 1995 Society for Neuroscience 0270-6474/95/l 53263-10$05.00/O glycerol (DAG). Activity at ionotropic EAA (NMDA) or NK-1 3264 Yashpal et al. * Protein Kinase C Activation by Noxious Stimuli receptors also stimulates the influx of calcium (Ca*+) through Materials and Methods NMDA receptor-operated Ca2+ channels (MacDermott et al., These experiments were performed on male, Long-Evans hooded rats 1986) and voltage-gated Ca2+ channels (Womack et al., 19X9), (Charles River) weighing 300-350 gm. They were maintained under respectively. Intracellular Ca*+ 1s also increased in response to controlled lighting conditions with food and water available ad libitum. the production of IP,, which promotes the release of intracellular The animals were divided into two groups; one group received noxious chemical stimulation, and the other group received noxious thermal Ca2+ from its stores within the endoplasmic reticulum (Womack stimulation. In all cases, the guidelines described in Cave and Use of et al., 1988). The increased Ca2+ influx and production of DAG Experimentul Animals of the Cum&m Council of Animal Care (Vols. are essential elements for the stimulation of various forms of the I, II) were strictly followed. enzyme protein kinase C (PKC) (Hug and Sarre, 1993), and likely explain why PKC activation is triggered by both EAA Physiological studies (Manzoni et al., 1990) and NK-I (Koizumi et al., 1992) receptor Formalin test. For chemical nociception, rats were given a subcutaneous activity. injection of 50 ~1 of 2.5% formalin into the plantar surface of one Activation of conventional forms of PKC by Ca*+ and DAG hindpaw. For nociceptive testing, animals were placed in a 30 X 30 X involves the translocation of the enzyme from a cytosolic loca- 30 cm Plexiglas box with a mirror below the surface at a 45” angle to allow an unobstructed view of the paws. Scoring of nociceptive behav- tion to a membrane-associated site (Hug and Sarre, 1993). Fol- iors began immediately after formalin injection and continued for 50 lowing translocation and activation, PKC phosphorylates spe- min. A nociceptive score was determined for each 5 min time block by cific substrate proteins that contribute to various cellular measuring the amount of time spent in each of the following behavioral processes, including neurotransmitter release and transduction categories: 0, the injected paw is not favored; I, the injected paw has (Nishizuka, 1986). These changes in synaptic transmission may little or no weight placed on it; 2, the injected paw is elevated and is not in contact with any surface; 3, the injected paw is licked, bitten, or account for findings that PKC contributes to various forms of shaken. A weighted average nociceptive score, ranging from 0 to 3, was neuronal plasticity including long-term potentiation (Malenka et calculated by multiplying the time spent in each category by the cate- al., 1986; Hu et al., 1987), neurotoxicity (Felipo et al., 1993), gory weight, summing these products, and then dividing by the total and cellular growth (Housey et al., 1988). The translocation and time for each 5 min time block. All the rats were acclimatized to the test chamber before testing began. Furthermore, in addition to extended activation of PKC has also been shown to be critical for memory observations of the rats, rats were assessed for possible motor dysfunc- processes including associative and discriminative learning tion by testing for placing and righting reflexes. (Olds et al., 1989, 1990). Assessment of mechanicul hyperalgesia after noxious thermal stim- The involvement of EAA and NK-1 receptors in both injury- ulution. The noxious thermal stimulus consisted of the immersion of induced neuronal plasticity and in the stimulation of intracellular one hindpaw into water maintained at 55°C for 15
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