Previous work from our lab showed that stimulation of the lateral hypothalamus (LH) produces analgesia (antinociception) in a model of thermal nociceptive pain. This antinociceptive effect is mediated by α2-adrenoceptors in the spinal cord dorsal horn. However, a concomitant, opposing hyperalgesic (pro-nociceptive) response also occurs, which is mediated by α1-adrenoceptors in the dorsal horn. Antinociception predominates but is attenuated by the pronociceptive response. To determine whether such an effect occurs in a model of inflammatory pain, we applied mustard oil (allyl isothiocyanate; 20 μl) to the left ankle of female Sprague-Dawley rats. We then stimulated the LH using carbamylcholine chloride (carbachol; 125 nmol). The foot withdrawal latencies were measured. Some rats received intrathecal α-adrenoceptor antagonists to determine whether the opposing α-adrenoceptor response was present. Mustard oil application produced hyperalgesia in the affected paw, while the LH stimulation increased the foot withdrawal latencies for the mustard oil paw as compared to the control group. Following carbachol microinjection in the LH, WB4101, an α1-adrenoceptor antagonist, produced significantly longer foot withdrawal latencies compared to saline controls, while yohimbine, an α2-antagonist, decreased the foot withdrawal latencies from 10 min postinjection (p < .05). These findings support the hypothesis that the LH-induced nociceptive modulation is mediated through an α-adrenoceptor opposing response in a model of inflammatory pain.
Aimone, L.D., & Gebhart, G.F. (1987). Spinal monoamine mediation of stimulation-produced antinociception from the lateral hypothalamus. Brain Research , 403, 290-300.
2.
Akopian, A., Ruparel, N., Jeske, N.A., & Hargreaves, K.M. (2007). Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. Journal of Physiology , 583(Pt. 1), 175-193.
3.
Bautista, D., Jordt, S.E., Nikai, T., Tsuruda, P.R., Read, A.J., Poblete, J., et al. (2006). TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell, 124, 1269-1282.
4.
Behbehani, M.M., Park, M.M., & Clements, M.E. (1988). Interactions between the lateral hypothalamus and the periaqueductal gray. Journal of Neuroscience, 8, 2780-2787.
5.
Brodie, M.S., & Proudfit, H.K. (1986). Antinociception induced by local injection of carbachol into the nucleus raphe magnus: Alteration by intrathecal injection of noradrenergic antagonists. Brain Research, 371, 70-79.
6.
Buhler, A.V., Proudfit, H.K., & Gebhart, G.F. (2004). Separate populations of neurons in the rostral ventromedial medulla project to the spinal cord and to the dorsolateral pons in the rat. Brain Research, 1016, 12-19.
7.
Burstein, R., Cliffer, K.D., & Giesler, G.J. (1987). Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon. Journal of Neuroscience , 7, 4159-4164.
8.
Burstein, R., Dado, R.J., Cliffer, K.D., & Giesler, G.J. (1991). Physiological characterization of spinohypothalamic tract neurons in the lumbar enlargement of rats. Journal of Neurophysiology, 66, 261-284.
9.
Cleland, C.L., Lim, F.Y., & Gebhart, G.F. (1994). Pentobarbital prevents the development of C-fiber-induced hyperalgesia in the rat. Pain, 57, 31-43.
Franco, A.C.J., & Prado, W.A. (1996). Antinociceptive effects of stimulation of discrete sites in the rat hypothalamus: Evidence for the participation of the lateral hypothalamus area in descending pain suppression mechanisms. Brazilian Journal of Medical Biological Research, 29, 1531-1541.
12.
Fuchs, P., & Melzack, R. (1995). Analgesia induced by morphine microinjection into the lateral hypothalamus of the rat. Experimental Neurology , 134, 277-280.
13.
Fuchs, P., Meyer, R.A., & Raja, S.N. (2001). Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin. Pain, 90, 15-23.
14.
Guo, W., Robbins, M., Wei, F., Zou, S., Dubner, R., & Ren, K. (2006). Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. Journal of Neuroscience, 26, 126-137.
15.
Han, S.R., Lee, M.K., Lim, K.H., Yang, G.Y., Jeon, H.J., Ju, J.S., et al. (2008). Intramuscular administration of morphine reduces mustard oil-induced craniofacial muscle pain behavior in lightly anesthetized rats. European Journal of Pain, 12, 361-370.
16.
Holden, J.E., Naleway, E., & Jeong, Y. (2005). Stimulation of the lateral hypothalamus produces antinociception mediated by 5-HT1A,5-HT1B and 5-HT3 receptors in the rat spinal cord dorsal horn. Neuroscience, 135, 1255-1268.
17.
Holden, J.E., & Naleway, E. (2001). Microinjection of carbachol in the lateral hypothalamus produces opposing actions on nociception mediated by α1- and α2 - adrenoceptors. Brain Research, 911, 27-36.
18.
Holden, J.E., Schwartz, E.J., & Proudfit, H.K. (1999). Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by α1- and α2 -adrenoceptors. Neuroscience , 91, 979-990.
19.
Hord, A., Denson, D., Stowe, B., & Haygood, R.M. (2001). Alpha-1 and alpha-2 adrenergic antagonists relieve thermal hyperalgesia in experimental mononeuropathy from chronic constriction injury. Anesthesia and Analgesia, 92, 1558-1562.
20.
Jeong, Y., Pizzi, J., & Holden, J.E. (2004). Stimulation of the lateral hypothalamus produces antinociception in inflammatory and neuropathic pain. Society for Neuroscience Abstracts, 30, 297-9.
21.
Jiang, M., & Gebhart, G.F. (1998). Development of mustard oil-induced hyperalgesia in rats. Pain, 77, 305-313.
22.
Kidd, B.L., & Urban, L.A. (2001). Mechanisms of inflammatory pain. British Journal of Anaesthesia, 87, 3-11.
23.
Klamt, J.G., & Prado, W.A. (1991). Antinociception and behavioral changes induced by carbachol microinjection into identified sites of the rat brain. Brain Research, 549, 9-18.
24.
Leite-Panissi, C.R., Brentegani, M.R., & Menescal-de-Oliveira, L. (2004). Cholinergic-opioidergic interaction in the central amygdala induces antinociception in the guinea pig. Brazilian Journal of Medical and Biological Research , 37, 1571-1579.
25.
Mansikka, H., & Pertovaara, A. (1997). Supraspinal influence on hind limb withdrawal thresholds and mustard oil-induced secondary allodynia in rats. Brain Research Bulletin, 42, 359-365.
26.
Millan, M. (1997). The induction of pain: an integrative review. Progress in Neurobiology, 57, 1-64.
27.
Millan, M. (2002). Descending control of pain. Progress in Neurobiology, 66, 355-474.
28.
Nicholas, A.P., Hokfelt, T., & Pieribone, V.A. (1996). The distribution and significance of CNS adrenoceptors examined with in situ hybridization. Trends in Pharmacological Science, 17, 245-255.
29.
Nuseir, K., & Proudfit, H.K. (2000). Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic neurons. Neuroscience, 96, 773-783.
30.
Park, S.J., Zhang, S., Chiang, C.Y., Hu, J.W., Dostrovsky, J.O., & Sessle, B.J. (2006). Central sensitization induced in thalamic nociceptive neurons by tooth pulp stimulation is dependent on the functional integrity of trigeminal brainstem subnucleus caudalis but not subnucleus oralis. Brain Research, 1112, 134-145.
31.
Pieribone, V.A., Nicholas, A.P., Dagerlind, A., & Hokfelt, T. (1994). Distribution of alpha 1 adrenoceptors in rat brain revealed by in situ hybridization experiments utilizing subtype-specific probes . Journal of Neuroscience, 14, 4252-4268.
32.
Pinto, M., Lima, D., & Tavares, I. (2007). Neuronal activation at the spinal cord and medullary pain control centers after joint stimulation: A c-fos study in acute and chronic articular inflammation. Neuroscience, 147, 1076-1089.
33.
Porreca, F., Ossipov, M.H., & Gebhart, G.F. (2002). Chronic pain and medullary descending facilitation . Trends in Neuroscience, 25, 319-325.
34.
Romero-Sandoval, E.A., & Eisenach, J.C. (2006). Perineural clonidine reduces mechanical hypersensitivity and cytokine production in established nerve injury . Anesthesiology, 104, 351-355.
35.
Romero-Sandoval, E.A., McCall, C., & Eisenach, J.C. (2005). Alpha2-adrenoceptor stimulation transforms immune responses in neuritis and blocks neuritis-induced pain. Journal of Neuroscience, 25, 8988-8994.
36.
Shannon, H.E., & Lutz, E.A. (2000). Yohimbine produces antinociception in the formalin test in rats: involvement of serotonin(1A) receptors. Psychopharmacology (Berl), 149, 93-97.
37.
Smith, V.A., Beyer, C.E., & Brandt, M.R. (2006). Neuro-chemical changes in the RVM associated with peripheral inflammatory pain stimuli. Brain Research, 1095, 65-72.
38.
Sweitzer, S.M., White, K.A., Dutta, C., & DeLeo, J.A. (2002). The differential role of spinal MHC class II and cellular adhesion molecules in peripheral inflammatory versus neuropathic pain in rodents. Journal of Neuroimmunology , 125, 82-93.
39.
Takano, Y., & Yaksh, T.L. (1992). Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. Journal of Pharmacology and Experimental Therapeutics, 26, 764-772.
40.
Traub, R. (1996). The spinal contribution of substance P to the generation and maintenance of inflammatory hyperalgesia in the rat. Pain, 67, 151-161.
41.
Trevisani, M., Siemens, J., Materazzi, S., Bautista, D.M., Nassini, R., Campi, B., et al. (2007). 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proceedings of the National Academy of Science U S A, 104, 13519-13524.
42.
Urban, M.O., & Gebhart, G.F. (1999). Central mechanisms in pain. Medical Clinics of North America, 83, 585-596.
43.
Urban, M.O., Jiang, M.C., & Gebhart, G.F. (1996). Participation of central descending nociceptive facilitatory systems in secondary hyperalgesia produced by mustard oil. Brain Research, 737, 83-91.
44.
Walker, S.M., & Fitzgerald, M. (2007). Characterization of spinal alpha-adrenergic modulation of nociceptive transmission and hyperalgesia throughout postnatal development in rats. British Journal of Pharmacology , 151, 1334-1342.
45.
Yaksh, T.L., Pogrel, J.W., Lee, Y.W., & Chaplan, S.R. (1995). Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. Journal of Pharmacology and Experimental Therapeutics, 272, 207-214.
46.
Yeomans, D.C., Clark, F.M., Paice, J.A., & Proudfit, H.K. (1992). Antinociception induced by electrical stimulation of spinally-projecting noradrenergic neurons in the A7 catecholamine cell group of the rat. Pain, 48, 449-461.
47.
Yeomans, D.C., & Proudfit, H.K. (1992). Antinociception induced by microinjection of substance P into the A7 catecholamine cell group in the rat. Neuroscience, 49, 681-691.
48.
Zhang, S., Chiang, C.Y., Xie, Y.F., Park, S.J., Lu, Y., Hu, J.W., et al. (2006). Central sensitization in thalamic nociceptive neurons induced by mustard oil application to rat molar tooth pulp. Neuroscience, 142, 833-842.
