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American Society for Action on Pain

UI - 000097

AU - Millan MJ

AU - Czlonkowski A

AU - Pilcher CW

AU - Almeida OF

AU - Millan MH

AU - Colpaert FC

AU - Herz A

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

AB - 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


SO - Journal of Neuroscience 1987;7:77-87