A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems

Intradermal inoculation of rats at the tail base with Mycobacterium butyricum led to the gradual development of an arthritic swelling of the limbs which peaked at 3 weeks and subsided thereafter. Arthritic rats displayed a loss of body weight, hypophagia, and hypodipsia in addition to a disruption of the diurnal rhythms of ingestive behavior and of core temperature. The activity of adenohypophyseal beta- endorphin-(beta-EP) secreting corticotrophs, in contrast to prolactin- (PRL) secreting lactotrophs, was increased in arthritic rats. Indeed, hypertrophy of the adrenal glands was seen. Arthritic rats also showed an elevation in spinal cord levels of immunoreactive dynorphin (DYN), an endogenous ligand of the kappa-opioid receptor. The paws and tail of arthritic rats showed lower thresholds in response to noxious pressure (hyperalgesia), higher thresholds in response to noxious heat (hypoalgesia), and no change in their response to noxious electrical stimulation. Neither naloxone nor ICI-154, 129 (a preferential delta- receptor antagonist) modified the responses of the paw or tail to pressure. However, MR 2266 (an antagonist with higher activity at kappa- receptors) decreased thresholds to pressure in arthritic, but not control, rats; that is, it potentiated the hyperalgesia. This action was stereospecific. None of the antagonists modified the response to heat. MR 2266 did not affect the response to pressure in rats with acute inflammation produced by yeast. Thus, the potentiation of pressure hyperalgesia by MR 2266 in chronic arthritic rats is highly selective. Arthritic rats showed a reduced response to the analgesic effect of a kappa-agonist (U-50,488H), whereas the response to a mu- agonist (morphine) was enhanced. These effects were specific to nociception in that their influence upon endocrine secretion (PRL and beta-EP) was otherwise changed. The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U- 50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats. It is suggested that polyarthritis is a complex condition entailing many changes, both behavioral and endocrinological. Further, arthritic rats cannot simply be described as “hyperalgesic”: of critical importance is the nature of the nociceptive stimulus applied. The parallel alterations in spinal cord pools of DYN and kappa-receptors (see also Millan et al., 1986) and the changes in the influence on nociception of kappa-agonists and kappa-antagonists suggest an increased activity of spinal DYN. Thus, spinal kappa- receptors may play a role in the modulation of nociception under chronic pain.(ABSTRACT TRUNCATED AT 400 WORDS)

[1]  A. Herz,et al.  Functional Response of Multiple Opioid Systems to Chronic Arthritic Pain in the Rat a , 1986, Annals of the New York Academy of Sciences.

[2]  A. Herz,et al.  A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  H. L. Wen,et al.  Intrathecal administration of beta-endorphin and dynorphin-(1-13) for the treatment of intractable pain. , 1985, Life sciences.

[4]  A. Herz,et al.  Spinal cord dynorphin may modulate nociception via a ℵ-opioid receptor in chronic arthritic rats , 1985, Brain Research.

[5]  H. Akil,et al.  Corticotropin-releasing factor stimulation of adrenocorticotropin and beta-endorphin release: effects of acute and chronic stress. , 1985, Endocrinology.

[6]  F. Holloway,et al.  Chronic stress, aging and morphine analgesia: chronic stress affects the reactivity to morphine in young mature but not old rats. , 1985, The Journal of pharmacology and experimental therapeutics.

[7]  B. Jacobs,et al.  Response of serotonin-containing neurons in nucleus raphe magnus to morphine, noxious stimuli, and periaqueductal gray stimulation in freely moving cats , 1985, Experimental Neurology.

[8]  G. Guilbaud,et al.  Can tolerance to morphine be induced in arthritic rats? , 1985, Brain Research.

[9]  S. Spampinato,et al.  Characterization of dynorphin A-induced antinociception at spinal level. , 1985, European journal of pharmacology.

[10]  K. Mack,et al.  Binding characteristics of kappa opioids in rat brain A comparison of in vitro binding paradigms , 1985, Neuropharmacology.

[11]  T. Priestley,et al.  In vivo evidence for the selectivity of ICI 154129 for the delta-opioid receptor , 1985, Neuropharmacology.

[12]  H. Akil,et al.  Induction of the intermediate pituitary by stress: synthesis and release of a nonopioid form of beta-endorphin. , 1985, Science.

[13]  Y. Shavit,et al.  Intrinsic mechanisms of pain inhibition: activation by stress. , 1984, Science.

[14]  S. Holtzman,et al.  Characterization of stress-induced potentiation of opioid effects in the rat. , 1984, The Journal of pharmacology and experimental therapeutics.

[15]  S. Maier,et al.  Exposure to uncontrollable stress alters withdrawal from morphine. , 1984, Behavioral neuroscience.

[16]  F. Artaud,et al.  Basic and Regulatory Mechanisms of In Vitro Release of Met‐Enkephalin from the Dorsal Zone of the Rat Spinal Cord , 1984, Journal of neurochemistry.

[17]  J. Han,et al.  Analgesia induced by intrathecal injection of dynorphin B in the rat. , 1984, Life sciences.

[18]  J. E. Sherman,et al.  Morphine analgesia: enhancement by shock-associated cues , 1984 .

[19]  K. Franklin,et al.  Evidence that stress augments morphine analgesia by increasing brain tryptophan , 1984, Neuroscience Letters.

[20]  T. Donohoe.  Stress-induced anorexia: implications for anorexia nervosa. , 1984, Life sciences.

[21]  P. Spano,et al.  Afferent fibers mediate the increase of met-enkephalin elicited in rat spinal cord by localized pain , 1984, Pain.

[22]  V. Höllt.  Multiple endogenous opioid peptides , 1983, Trends in Neurosciences.

[23]  J. Jacob,et al.  Local inhibition of inflammatory pain by naloxone and its N-methyl quaternary analogue. , 1983, European journal of pharmacology.

[24]  H. Takagi,et al.  Separate involvement of the spinal noradrenergic and serotonergic systems in morphine analgesia: the differences in mechanical and thermal algesic tests , 1983, Brain Research.

[25]  K. Hole,et al.  Attenuation of morphine-induced analgesia by p-chlorophenylalanine and p-chloroamphetamine: Test-dependent effects and evidence for brainstem 5-hydroxytryptamine involvement , 1983, Brain Research.

[26]  J. Y. Wang,et al.  Studies on the release by somatic stimulation from rat and cat spinal cord of active materials which displace dihydromorphine in an opiate-binding assay , 1983, Brain Research.

[27]  G. Guilbaud,et al.  The analgesic effects of morphine, but not those of the enkephalinase inhibitor thiorphan, are enhanced in arthritic rats , 1983, Brain Research.

[28]  F. Lembeck,et al.  Effects of capsaicin on inflammation and on the substance P content of nervous tissues in rats with adjuvant arthritis. , 1983, Life sciences.

[29]  G. Guilbaud,et al.  Low dose of morphine strongly depresses responses of specific nociceptive neurones in the ventrobasal complex of the rat , 1983, Pain.

[30]  J. Barchas,et al.  Predominance of the amino-terminal octapeptide fragment of dynorphin in rat brain regions , 1982, Nature.

[31]  J. Morley,et al.  Selective antagonists at the opiate delta-receptor. , 1982, Life sciences.

[32]  D. Menétrey,et al.  Electrophysiological characteristics of dorsal horn cells in rats with cutaneous inflammation resulting from chronic arthritis , 1982, PAIN®.

[33]  G. Guilbaud,et al.  Effects of systemic naloxone upon ventrobasal thalamus neuronal responses in arthritic rats , 1982, Brain Research.

[34]  L. Watkins,et al.  Organization of endogenous opiate and nonopiate pain control systems. , 1982, Science.

[35]  G. Guilbaud,et al.  Somatic responses of ventrobasal thalamic neurones in polyarthritic rats , 1982, Brain Research.

[36]  A. Barnett,et al.  Relationship of yeast-injection induced changes in brain Met-enkephalin and analgesia , 1982, Peptides.

[37]  G. Guilbaud,et al.  Dose-dependent analgesic and hyperalgesic effects of systemic naloxone in arthritic rats , 1981, Brain Research.

[38]  I. Vermes,et al.  Hypothalamic deafferentation in the rat appears to discriminate between the anterior lobe and intermediate lobe response to stress , 1981, Neuroscience Letters.

[39]  T. Yaksh,et al.  Factors governing release of methionine enkephalin-like immunoreactivity from mesencephalon and spinal cord of the cat in vivo. , 1981, Journal of neurophysiology.

[40]  R. Schulz,et al.  The preference of putative pro-enkephalins for different types of opiate receptors. , 1981, Life sciences.

[41]  R. Przewłocki,et al.  The influence of foot-shock stress upon brain, pituitary and spinal cord pools of immunoreactive dynorphin in rats , 1981, Neuroscience Letters.

[42]  J. E. Sherman,et al.  Opioid and non-opioid stress analgesia: assessment of tolerance and cross-tolerance with morphine , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[43]  A. Herz,et al.  Stress-induced release of brain and pituitary β-endorphin: Major role of endorphins in generation of hyperthermia, not analgesia , 1981, Brain Research.

[44]  J. Montastruc,et al.  Met-enkephalin levels and opiate receptors in the spinal cord of chronic suffering rats , 1980, Brain Research.

[45]  Z. Boulos,et al.  Food availability and daily biological rhythms , 1980, Neuroscience & Biobehavioral Reviews.

[46]  C. Niemegeers,et al.  The effects of prior fentanyl administration and of pain on fentanyl analgesia: tolerance to and enhancement of narcotic analgesia. , 1980, The Journal of pharmacology and experimental therapeutics.

[47]  J. Besson,et al.  Changes in brain and spinal tryptophan and 5-hydroxy-indoleacetic acid levels follwing acute morphine administration in normal and arthritic rats , 1979, Brain Research.

[48]  F. Colpaert,et al.  Can chronic pain be suppressed despite purported tolerance to narcotic analgesia? , 1979, Life sciences.

[49]  F. Bloom,et al.  β-ENDORPHIN AND ADRENOCORTICOTROPIN ARE SECRETED CONCOMITANTLY BY THE PITUITARY GLAND , 1978 .

[50]  F. Bloom,et al.  beta-Endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland. , 1977, Science.

[51]  N. Kley,et al.  Stress-induced alterations in the levels of messenger RNA coding for proopiomelanocortin and prolactin in rat pituitary. , 1986, Neuroendocrinology.

[52]  L. Krulich,et al.  Opioid kappa receptors and the secretion of prolactin (PRL) and growth hormone (GH) in the rat. I. Effects of opioid kappa receptor agonists bremazocine and U-50,488 on secretion of PRL and GH: comparison with morphine. , 1986, Neuroendocrinology.

[53]  M. Millan,et al.  The endocrinology of the opioids. , 1985, International review of neurobiology.

[54]  J. Morley,et al.  Peptidergic regulation of feeding. , 1985, International review of neurobiology.

[55]  A I Basbaum,et al.  Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. , 1984, Annual review of neuroscience.

[56]  R. Lahti,et al.  U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist. , 1983, The Journal of pharmacology and experimental therapeutics.

[57]  L. Terenius,et al.  Opioid activity released from cat spinal cord by sciatic nerve stimulation. , 1983, Life sciences.

[58]  R. Przewłocki,et al.  Analgesic effects of μ-, δ- and κ-opiate agonists and, in particular, dynorphin at the spinal level , 1983 .

[59]  M. Millan.  Stress and endogenous opioid peptides: a review. , 1981, Modern problems of pharmacopsychiatry.

[60]  P. Brazeau,et al.  Effects of chronic immobilization stress on pituitary hormone secretion, on hypothalamic factor levels, and on pituitary responsiveness to LHRH and TRH in female rats. , 1979, Neuroendocrinology.

[61]  H. Kosterlitz,et al.  Opiate receptors , 1976, Nature.