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Chronic pain in the rat: Selective alterations in CNS and pituitary pools of dynorphin as compared to vasopressin
Neuropeptides
5
423-.424,
1985
CHRONIC PAIN IN THE RAT: SELECTIVE ALTERATIONS IN CNS AND PITUITARY POOLS OF DYNORPHIN AS COMPARED TO VASOPRESSIN M.J. Millan , M.H. Millan', C.W.T.Pilcher',F.C. Colpaert*and A. Hers1 'Department of Neuropharmacolcgy, Max-Plan&-Institutefor Psychiatry, Am Klopferspitz18a, D-8033 Planegg-Martinsried, F.R.G. 2 Departmentof Pharmacology,Janssen Pharmaceutics,B-Beerse,Belgium. ABSTRACT
Inoculationof rats at the tail-basewith Mymbacterium led to arthritic swellingand inflanunation of all four limbs. Irmunoreactive(ir)-dynorphin (DYN)increasedin anteriorbut hot neurointermediate pituitary.In the brain, only thalamusshowed a rise and, in spinal axd, a large elevationwas seen. Ir-vasopressin(VP)was not affected in these tissuesbut increasedin midbrain. These effects might reflect a role of DYN in the controlof chronic 7 pain. In addition,they supporta differentialmdulation of DYN as cmparec to VP extrinsicto the hypothalamic-neurohypophyseal axis. INTRODUCTION It is possible that DYN modulatesnociceptionvia K-receptorsat the Spinal level in the rat (1,2,3).DiscreteCNS and pituitarypools of ir-DYN are mdulated by acute pain (foot-shock)and K-receptorsmay partiallymediate such stress-relatedantinocicepticm(4,5,6).Acute pain also affectsCNS pools of ir-VP (5), a peptide with antimciceptive properties.(7).We suggestedthat DYN and VP are co-localizedand co-rmdulatedin the hypothalamic-neurohyfmphyseal axis but -. mt extrinsicto this (5,8).We thereforeevaluatedthe comparative responseof ir-DYN and ir-VP to chronic pain in the rat. METHODS Rats were inoculatedintrademally at the tail-basewith killed,Mycobacteriumbutyrimanddecapitatedat3weeks. Levelsof ir-DYNand ix-VP in discretetissueswere detennined by specificRIA's (4,5,8).Data are given as percentagerise in pain rats relativeto controls. RESULTS
Rats showed a swellingand inflammationof limbs which ware hyperalgesic to pressure (45.2+ 3.6% fall in threshold).Ir-DYN rose in anterior (42.6+ 7.4%) but not neur&ntemediate pituitary.In brain, only the thalalnu~ se a rise by 62.1 2 7r8%. In lurr$m-sacral spinal cord, a large rise of ir-DYN by 167.8 + 12.4% was observed.In contrast,ir-VP was not changed in these regions but was elevated in the midbrainby 38.9 + 4.2%. All changes specifiedwere significanton t-test analysisof raw data (p < 0.005, in each case). 423
DISCUSSION
Acute pain depletes spinal cord and anteriorbut not neurointemadiate pituiwir-DYN, presmmbly reflectingrelease (4,5).The present data reveal canparablyselectiveaffectsof chronicpain with the rises probablydue to increasedsynthesis.Thus both acute and chronicpain may activatethese DYNsystems.Further, in spinal cord, DYN might act to 'modulate chronic pain since a) at the spinal level, K-agonists(includingintrathecalDYN) act antimciceptively againstpressure (1,2,3),b) the rise in spinal ir-DYN correlated with intensityof arthritisand hyperalgesiaand c) MR-2266,a preferential K-antaqnist, potentiatedthis hyperalgesia(3).F’urthm, the rise in ir-DYN in the thalamusmay be related to the alteredresponseto opioid antagonists shown by thalamicneurones in arthriticrats (9).Mxeover, the midbrain is involvedin mciceptive processesand the rise in VP (whichacts antimciceptively in brain (8))thereinmay be functionallyrelatedto the responseto chronicpain. Finally, in analogy to acute pain (5), ir-DYN and ir-VP are affecteddiffe rentiallyby chronic pain, iZiZe with studies suggestingthat co-localization andco-mdulationof DYNandVPis peculiarto thehypothalam-neurohypophyseal axis and axis, elsewhere,they are modulatedand localizedindependently(5,8).
R., Stala, L., Greczek,M. et al. (1983).Analgesiceffectsof 1. Przewkcki, p, b- and K-opiateagonistsandinparticular, dynorphin,at the spinal level.Life Sciences33, Supplenx=nt 1:649-652. 2. Kaneko, T., Nakazawa,T., Ikeda,K. et al. (1983). Sites of analgesicaction of dymrphin. Life Sciences33, Supplement1:661-664. 3. Pilcher,C.W.T. and Millan, M.J., unpublishedand in preparation. 4. Millan,M.J., Tsang, Y.F., Prze-i, R. et al. (1981).The influenceof foot-shockstress upon brain, pituitaryand spinal cord pools of imunoreactivedynorphinin the rat. NeuroscienceIetters 24:75-79. 5. Millan,M.J., Millan, M.H., Tsang, Y.F. and Herz, A. (1983).Reqonse of brain and pituitarypools of dynorphinas comparedto vasopressinto acute stress in the rat, Life Sciences33, Supplsmnt 1:29-32. A., Sacer&ote,P. and Mantegazza,P. (1984).K6. Panerai,A.E., -, receptoragonist reverses 'non-opioid'stress-inducedanticiception,Brain Research,in press. 7. Bodnar, R.J., Wallace,M.M., Kordower,J.H. et al. (1982).mulation of mciceptive threshaldbyvasopressin intheBrattleimro andrmmalrat. Annals New York Academy of Science 394:735-744. 8. Millan,M-H., Millan, M.J. ti Herz, A. (1984).The paraventricularnucleus: relationshipto brain and pituitarypools of vasopressinand oxytocin as ccmparedto B-en&zphin, dynorphinand relatedopioid peptides in the rat. Neuroe&xrimlcgy 38:108-116. 9. Guilbard,G., Benoist,J.M., Gautron,M. and Kayser,V. (1982).Effect of systtmicnaloxoneuponventro-basalthalamusne&onalrespons.esinarthritix rats. Brain Research 243:59-66.
424
5
423-.424,
1985
CHRONIC PAIN IN THE RAT: SELECTIVE ALTERATIONS IN CNS AND PITUITARY POOLS OF DYNORPHIN AS COMPARED TO VASOPRESSIN M.J. Millan , M.H. Millan', C.W.T.Pilcher',F.C. Colpaert*and A. Hers1 'Department of Neuropharmacolcgy, Max-Plan&-Institutefor Psychiatry, Am Klopferspitz18a, D-8033 Planegg-Martinsried, F.R.G. 2 Departmentof Pharmacology,Janssen Pharmaceutics,B-Beerse,Belgium. ABSTRACT
Inoculationof rats at the tail-basewith Mymbacterium led to arthritic swellingand inflanunation of all four limbs. Irmunoreactive(ir)-dynorphin (DYN)increasedin anteriorbut hot neurointermediate pituitary.In the brain, only thalamusshowed a rise and, in spinal axd, a large elevationwas seen. Ir-vasopressin(VP)was not affected in these tissuesbut increasedin midbrain. These effects might reflect a role of DYN in the controlof chronic 7 pain. In addition,they supporta differentialmdulation of DYN as cmparec to VP extrinsicto the hypothalamic-neurohypophyseal axis. INTRODUCTION It is possible that DYN modulatesnociceptionvia K-receptorsat the Spinal level in the rat (1,2,3).DiscreteCNS and pituitarypools of ir-DYN are mdulated by acute pain (foot-shock)and K-receptorsmay partiallymediate such stress-relatedantinocicepticm(4,5,6).Acute pain also affectsCNS pools of ir-VP (5), a peptide with antimciceptive properties.(7).We suggestedthat DYN and VP are co-localizedand co-rmdulatedin the hypothalamic-neurohyfmphyseal axis but -. mt extrinsicto this (5,8).We thereforeevaluatedthe comparative responseof ir-DYN and ir-VP to chronic pain in the rat. METHODS Rats were inoculatedintrademally at the tail-basewith killed,Mycobacteriumbutyrimanddecapitatedat3weeks. Levelsof ir-DYNand ix-VP in discretetissueswere detennined by specificRIA's (4,5,8).Data are given as percentagerise in pain rats relativeto controls. RESULTS
Rats showed a swellingand inflammationof limbs which ware hyperalgesic to pressure (45.2+ 3.6% fall in threshold).Ir-DYN rose in anterior (42.6+ 7.4%) but not neur&ntemediate pituitary.In brain, only the thalalnu~ se a rise by 62.1 2 7r8%. In lurr$m-sacral spinal cord, a large rise of ir-DYN by 167.8 + 12.4% was observed.In contrast,ir-VP was not changed in these regions but was elevated in the midbrainby 38.9 + 4.2%. All changes specifiedwere significanton t-test analysisof raw data (p < 0.005, in each case). 423
DISCUSSION
Acute pain depletes spinal cord and anteriorbut not neurointemadiate pituiwir-DYN, presmmbly reflectingrelease (4,5).The present data reveal canparablyselectiveaffectsof chronicpain with the rises probablydue to increasedsynthesis.Thus both acute and chronicpain may activatethese DYNsystems.Further, in spinal cord, DYN might act to 'modulate chronic pain since a) at the spinal level, K-agonists(includingintrathecalDYN) act antimciceptively againstpressure (1,2,3),b) the rise in spinal ir-DYN correlated with intensityof arthritisand hyperalgesiaand c) MR-2266,a preferential K-antaqnist, potentiatedthis hyperalgesia(3).F’urthm, the rise in ir-DYN in the thalamusmay be related to the alteredresponseto opioid antagonists shown by thalamicneurones in arthriticrats (9).Mxeover, the midbrain is involvedin mciceptive processesand the rise in VP (whichacts antimciceptively in brain (8))thereinmay be functionallyrelatedto the responseto chronicpain. Finally, in analogy to acute pain (5), ir-DYN and ir-VP are affecteddiffe rentiallyby chronic pain, iZiZe with studies suggestingthat co-localization andco-mdulationof DYNandVPis peculiarto thehypothalam-neurohypophyseal axis and axis, elsewhere,they are modulatedand localizedindependently(5,8).
R., Stala, L., Greczek,M. et al. (1983).Analgesiceffectsof 1. Przewkcki, p, b- and K-opiateagonistsandinparticular, dynorphin,at the spinal level.Life Sciences33, Supplenx=nt 1:649-652. 2. Kaneko, T., Nakazawa,T., Ikeda,K. et al. (1983). Sites of analgesicaction of dymrphin. Life Sciences33, Supplement1:661-664. 3. Pilcher,C.W.T. and Millan, M.J., unpublishedand in preparation. 4. Millan,M.J., Tsang, Y.F., Prze-i, R. et al. (1981).The influenceof foot-shockstress upon brain, pituitaryand spinal cord pools of imunoreactivedynorphinin the rat. NeuroscienceIetters 24:75-79. 5. Millan,M.J., Millan, M.H., Tsang, Y.F. and Herz, A. (1983).Reqonse of brain and pituitarypools of dynorphinas comparedto vasopressinto acute stress in the rat, Life Sciences33, Supplsmnt 1:29-32. A., Sacer&ote,P. and Mantegazza,P. (1984).K6. Panerai,A.E., -, receptoragonist reverses 'non-opioid'stress-inducedanticiception,Brain Research,in press. 7. Bodnar, R.J., Wallace,M.M., Kordower,J.H. et al. (1982).mulation of mciceptive threshaldbyvasopressin intheBrattleimro andrmmalrat. Annals New York Academy of Science 394:735-744. 8. Millan,M-H., Millan, M.J. ti Herz, A. (1984).The paraventricularnucleus: relationshipto brain and pituitarypools of vasopressinand oxytocin as ccmparedto B-en&zphin, dynorphinand relatedopioid peptides in the rat. Neuroe&xrimlcgy 38:108-116. 9. Guilbard,G., Benoist,J.M., Gautron,M. and Kayser,V. (1982).Effect of systtmicnaloxoneuponventro-basalthalamusne&onalrespons.esinarthritix rats. Brain Research 243:59-66.
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