(683)

Abstracts (681) FMRI evidence of noxious thermal stimuli encoding in the human spinal cord S Mackey, A Lucca, D Soneji, K Kaplan, G Glover; Stanford University, Palo Alto, CA Functional magnetic resonance imaging (fMRI) has been used to investigate nociceptive processing and central sensitization in the brain. The spinal cord is important in the processing of nociception and in the generation and maintenance of hyperalgesia/allodynia. The goal of this study was to use human spinal fMRI to investigate nociceptive processing within the human spinal cord. Our hypothesis was that: increases in noxious thermal stimuli will produce a corresponding increase in fMRI signal activation in the human spinal dorsal horn and increases in spatial and rostrocaudal activity. Following IRB approval, 10 healthy adults were recruited. Subjects were scanned in a 3T GE MRI system using a custom built cervical spine surface coil. Stimuli were delivered using a block design trial alternating 30 sec blocks of either 46°C, 47°C, or 48°C with 32°C of warmth. Functional scans were collected in each subject from the top of C5 through the bottom of C7. Functional images were retrospectively corrected to reduce noise created by the respiratory cycle and cardiac pulsatility. The data were then analyzed to measure both voxel significance and percent blood oxygen level dependent (BOLD) changes. Spinal fMRI activity to noxious stimuli was well localized to the ipsilateral superficial and deep dorsal horn at the spinal cord level corresponding to the dermatomal region stimulated. There was an increasing fMRI BOLD signal in the dorsal horn associated with increasing magnitude of thermal stimuli. Additionally, with increasing thermal stimuli there were both increases in rostro-caudal extension of dorsal horn activity as well as increases in contralateral dorsal horn activity. These results support our hypothesis and suggest that both population coding and changes in individual voxel activation in the spinal cord play a role in encoding pain intensity in humans. This is consistent with animal models of spinal cord nociceptive processing.

S25 (683) Central projections of primary afferent neurons that innervate the deep and cutaneous orofacial structures: A double retrograde tracing study H Wang; University of Maryland, Baltimore, MD Society for Neuroscience abstract

(684) Effect of interleukin-1beta on NR1-serine 896 phosphorylation in the rat spinal trigeminal nucleus W. Goo; University of Maryland, Baltimore, MD Society for Neuroscience abstract

(685) Refer to Oral Paper Session 318

B19 - Trigeminal Pain Mechanisms

B30 - Other

(682) MCP-1/CCL2 and CCR2 upregulation following partial ligation of the infraorbital nerve: possible involvement in the development and maintenance of trigeminal neuralgia

(686) Tapentadol HCl: In vitro and in vivo studies on the dual mechanism of action underlying its broad analgesic profile

F White, W Bauer, W Jellish, D Chan, R LaMotte, R Miller; Northwestern University, Chicago, IL Chemokines contribute to inflammation and, as we have recently found, may also enhance the excitability of nociceptive sensory neurons after an injury of the spinal ganglion. However, little is known of the role of chemokines following an injury of a trigeminal nerve which results in chronic pain. In the present study, we investigated the degree to which partial ligation of the infraorbital nerve (IoN) produces tactile hyperalgesia and changes in chemokines/receptors. To assess neuropathic pain in rats, we examined the degree to which partial ligation of the IoN modifies mechanical sensitivity as measured by changes in the threshold force of indentation (produced by von Frey filaments) necessary for eliciting a nociceptive response. Behavioral analysis revealed that stimulus-evoked behavioral response is first observed on post-operative day (POD-3). This initial behavioral response was significantly increased above baseline threshold in the extra-territorial areas adjacent to the termination sites of the IoN (OS). Areas within the termination sites of the IoN (IS) did not become reach the same level of significance until POD-7. Stimulus-evoked behavioral responses in the IoN areas of innervation contralateral to the injured IoN exhibited changes similar to behavioral response time-line of ipsilateral IS. Sham injury did not produce changes in behavioral response to von Frey stimulation. In situ hybridization performed on tissue sections taken from POD-7 and POD-14 trigeminal ganglion (TRG) exhibited ␤ chemokine C-C receptor-2 (CCR2) mRNA in neurons only. Receptor upregulation was present in ganglia ipsi- and contralateral to injury. We also determined that many sizes of TRG neurons exhibited strong expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) protein. Taken together, it is possible that the injury-induced neuronal production of MCP-1 may influence excitation in neurons bearing the CCR2 receptor. Reduction in neuronal MCP-1 could lessen the hyperexcitable states of neurons following partial ligation of IoN.

T Tzschentke, J De Vry, T Christoph, B Koegel, H Hennies, W Englberger, T Cremers, U Jahnel; Gruenenthal GmbH, Aachen, Germany Tapentadol HCl [(⫺)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode analgesic with ␮-opioid receptor (MOR) agonism and norepinephrine (NE) reuptake inhibition. The compound had a Ki of 0.1 ␮M in a rat MOR binding assay, and a relative efficacy of 88% (compared to morphine) in a functional [35S]GTP␥S binding assay. There was at least 10-fold selectivity over other opioid receptors (delta, kappa, ORL1). In addition, tapentadol HCl inhibited the NE reuptake transporter with a Ki of 0.5 ␮M (in a rat synaptosomal reuptake assay). In vivo brain microdialysis studies in the ventral hippocampus of freely moving rats showed that tapentadol HCl produces large increases in extracellular levels of NE (up to 450% above baseline) in the analgesic dose range, confirming the functional in vivo relevance of the NE transporter inhibition. In contrast, the prototypical opioid morphine produced only marginal effects on NE levels. The noradrenergic contribution to the dual mode of action of tapentadol HCl was demonstrated in the spinal nerve ligation rat model of chronic neuropathic pain. Equianalgesic doses of tapentadol HCl and morphine were combined with fixed doses of the ␣2-NE receptor antagonist yohimbine and the MOR antagonist naloxone. It was found that the analgesic effect of tapentadol HCl was strongly antagonized by yohimbine but only weakly affected by naloxone, whereas the opposite was the case for morphine. The greater sensitivity of morphine analgesia towards naloxone antagonism was confirmed in the mouse phenylquinone writhing model, where naloxone antagonized the analgesic effect of morphine much more potently than the analgesic effect of tapentadol HCl, implying an additional naloxone-insensitive component in the latter drug. Taken together, the data support the suggestion that the broad analgesic profile of tapentadol HCl is based on the combination of MOR activation and NE reuptake inhibition.