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Under intact and spinalized conditions, we compared the responses of deep spinal dorsal horn (DH) nociceptive-specific (NS) and wide-dynamic range (WDR) neurons to subcutaneous bee venom (BV, 0.2 mg/50 microl)-induced persistent nociception. In contrast to the monophasic, long-lasting (34-81 min) WDR neuron responses in both intact and spinalized conditions, BV in NS neurons elicited short-term (<10 min) firing in intact, and long-term (>1 h) biphasic firing in spinalized rats. The BV-induced long-term biphasic NS neuron activities in spinalized condition consisted of a first, early phase (4-13 min) of firing occurred immediately after the BV injection, and a second phase of tonic firing that lasted for 28-74 min. The two phases were separated by a period that lasted 4-11 min during which there was very little neuronal activity. The data suggest that in the presence of peripheral nociception, a transitory (about 5-13 min) spinal segmental inhibitory control and a long-lasting descending inhibitory control govern deep spinal NS neuron but not WDR neuron activity. Previous reports assessing spinally organized motor activities showed a spinal WDR neuron well-controlled monophasic long-lasting withdrawal reflex in response to BV injection in both intact and spinalized conditions. In contrast, the current data suggest that unlike spinal WDR neurons, deep spinal DH NS neurons do not modulate spinal motor output during the persistent nociception. Using the neurokinin-1 (NK-1) receptor antagonist, L-703,606 we further found that only early (within 15 min) treatment with L-703,606 produced a significant inhibition of the enhanced mechanically evoked NS neuron responses in BV-induced nociception, suggesting a dynamic function of NK-1 receptor involvement for deep spinal NS neuron mediated central sensitisation. We conclude that deep spinal DH NS neurons are strictly governed by tonic inhibitory descending controls. As this descending inhibitory control either is absent or decays, deep spinal NS neurons may play a crucial role in the development of central sensitisation in pathological nociception, for instance in spinal cord injury-induced pathological pain.

High-efficacy activation of central 5-HT(1A) receptors by means of the recently discovered, selective 5-HT(1A) receptor ligand, F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral infraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation - within 24 days; thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT(1A) receptors may be involved in the dynamical, dose- and time-dependent, pre-treatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT(1A) receptor activation.

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.

Guided by an understanding of signal transduction in pain-processing systems, high-efficacy 5-hydroxytryptamine (5HT)1A receptor activation, by means of F-13640, has been discovered as a new molecular mechanism of pain relief in laboratory animals, inducing two neuroadaptive phenomena. Firstly, this activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and secondly, inverse tolerance develops so that the resulting analgesia grows rather than decays. As an apparent result of these novel neuroadaptive mechanisms, F-13640 exerts an analgesic action in rat models of acute, tonic and chronic nociceptive pain that is rivaled only by large doses of high-efficacy mu-opioid receptor agonists. In models of neuropathic allodynia of peripheral or central origin, chronic F-13640 administration causes an analgesia that surpasses that observed with morphine or other agents exemplifying other central nervous system drug mechanisms of pain relief (e.g., ketamine, imipramine and gabapentin). Indeed, F-13640 produces long-lasting, preemptive and, most remarkably, curative-like actions in neuropathic allodynia. Although awaiting proof-of-concept evidence in humans, high-efficacy 5-HT(1A) receptor activation may uniquely challenge the opioids for pain therapy.

F 13640 is a newly discovered high-efficacy 5-HT(1A) receptor agonist that produces exceptional analgesia in animal models of tonic and chronic, nociceptive and neuropathic pains by novel molecular and neuroadaptive mechanisms. Here we examined the effects of F 13640 and remifentanil (0.63 mg/kg with either compound) when injected i.p. either before or 15 min after rats underwent orthopedic surgery. Surgery consisted of the drilling of a hole in the calcaneus bone and of an incision of the skin, fascia and plantar muscle of one foot. During surgery, the concentration of volatile isoflurane was progressively incremented depending on the animal's response to surgical maneuvers. Other experiments examined the dose-dependent effects of F 13640 (0.04 to 0.63 mg/kg) on surgical pain as well as on the Minimum Alveolar Concentration of isoflurane. Both F 13640 and remifentanil markedly reduced the intra-operative isoflurane requirement. F 13640 also reduced measures of postoperative pain (i.e., paw elevation and flexion). With these postoperative measures, remifentanil produced short-lived analgesia followed by hyperalgesia. F 13640 significantly reduced both surgical pain and the isoflurane Minimum Alveolar Concentration from 0.16 mg/kg onward. F 13640 produced powerful intra- and postoperative analgesia in rats undergoing orthopedic surgery. Unlike the opioid, remifentanil, F 13640 caused no hyperalgesia with ongoing postoperative pain, and should remain effective with protracted postoperative use.

The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.

We here studied the involvement of spinally located 5-HT(1A) and opioid receptors, in the paradoxical effects that their activation can produce on nociception. Intrathecal (i.t.) injection of the 5-HT(1A) receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT) (1-10 microg) induced analgesic effects in the formalin model of tonic pain whereas in the paw pressure test, it decreased the vocalization threshold. In this latter test, i.t. 8-OH-DPAT also markedly reduced the analgesic effect of systemic morphine (5-10 mg/kg, s.c.). At 10 microg, 8-OH-DPAT totally abolished the effect of 5 mg/kg of morphine; this inhibitory effect was antagonized by pre-treatment with 0.63 mg/kg of the 5-HT(1A) antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)-cyclohexanecarboxamide-trihydrochloride). In contrast, the i.t. injection of WAY-100635 (1-10 microg) dose-dependently potentiated the antinociceptive activity of a dose of morphine (2.5 mg/kg, s.c.). Furthermore, WAY-100635 (10 microg, i.t.) potentiated morphine analgesia in morphine-tolerant rats. These findings demonstrate that 5-HT(1A) receptor agonists can act in the spinal cord to produce both hyper- and hypo-algesic effects and play a major role in the opioid analgesia and tolerance.

Central neuropathic pain after spinal cord injury (SCI) presents a challenging clinical problem with limited treatment options. [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]]-methadone (F 13640) is a recently discovered very-high-efficacy, selective 5-HT1A receptor agonist that produces a remarkably powerful, central analgesia through unprecedented neuroadaptive mechanisms. In a rat model of spinal cord injury pain, we previously found that chronic infusion of F 13640 alleviated pain-like behaviors. Here, we report that infusion of 0.63 mg/day of F 13640 for 8 weeks starting 24 h before the induction of injury significantly attenuates the development of chronic allodynia-like behavior in rats sustaining a photochemically-induced, ischaemic injury of the dorsal laminae of the L3-L5 segments of the spinal cord. Importantly, the preemptive effect of F 13640 persisted for 2 months after treatment was discontinued. The data warrant the study of the possible effects of the early administration of F 13640 in patients sustaining spinal cord injury.

(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone (F 13640) is a recently discovered high-efficacy 5-hydroxytryptamine (HT)1A receptor agonist that produces central analgesia through the neuroadaptive mechanisms of inverse tolerance and cooperation. In a rat model of trigeminal neuropathic pain, the chronic constriction injury of the infraorbital nerve causes allodynia-like behavior that develops within 2 weeks and remains stable thereafter. We report that early after surgery, during which time allodynia develops, the continuous 2-week infusion of 0.63 mg/day F 13640 inhibited the allodynia-like behavior, whereas 5 mg/day morphine showed no significant effect. When F 13640 infusion was initiated late after surgery, when allodynia was well established, it produced an antiallodynic effect that was apparent during the entire infusion period. In contrast, morphine infusion caused an initially marked antiallodynic effect to which tolerance developed within the 2-week infusion period. The GABA-B receptor agonist baclofen (1.06 mg/day) that has a recognized usefulness in the treatment of trigeminal neuralgia, demonstrated effectiveness in both conditions. The data are consistent with a theory of nociceptive signal transduction, as well as with previous data, in demonstrating the neuroadaptive mechanisms of inverse tolerance and cooperation. That is, in contrast with morphine, the antiallodynic effect induced by 5-HT1A receptor activation does not decay, but, if anything, grows with chronicity. Also, 5-HT1A receptor activation seemed to cooperate with nociceptive stimulation in, paradoxically, inducing an antiallodynic effect. The data presented here suggest that F 13640 may perhaps offer a lasting treatment of trigeminal neuralgia.

The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain.

The experiments examined antinociceptive and intrinsic behavioral effects induced by the prototypical 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino] tetralin) in rats. 8-OH-DPAT (0.01-2.5 mg/kg, subcutaneous (s.c.)) reduced both the paw licking and paw elevation induced by (2.5%) formalin injection into the plantar surface of the right hindpaw; it also produced forepaw treading. All of these effects were completely blocked by pretreatment with WAY 100635 (N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (0.16 mg/kg, s.c.); prazosin (0.63 mg/kg, s.c.) inhibited forepaw treading, but not 8-OH-DPAT's action on paw elevation and paw licking. Repeated injection of 8-OH-DPAT (0.63 mg/kg, s.c.) twice daily for 4 days, markedly reduced 8-OH-DPAT's ability to produce forepaw treading, but exerted only little and inconsistent effects on its paw licking and paw elevation-inhibiting action. The data indicate that 8-OH-DPAT exerts an analgesic action in the formalin model of tonic nociceptive pain; this action is mediated by 5-HT(1A) receptors, and is not confounded by the productive sign (i.e., forepaw treading) of the 5-HT syndrome which 8-OH-DPAT also induces.

One day after intraplantar inoculation of Mycobacterium butyricum into the right hind-paw, unilaterally inflamed and control rats were implanted subcutaneously with osmotic mini-pumps delivering naloxone at 0.16 or 3.0 mg/kg/h or vehicle. As determined three days after implantation, 0.16 mg/kg/h of naloxone completely antagonized the antinociceptive action of the mu-agonist, morphine, but did not affect antinociception evoked by the kappa-agonist, U69,593. In contrast, at 3.0 mg/kg/h, naloxone blocked both morphine- and U69,593-induced antinociception. Thus, 0.16 mg/kg ("low dose") and 3.0 mg/kg ("high dose") of naloxone block mu, or mu- plus kappa-opioid receptors, respectively. Pumps were removed one week following their implantation. Inoculation was associated with a sustained hyperalgesia of the inflamed paw to noxious pressure, and elevation in resting core temperature, a loss of body weight, hypophagia, hypodipsia and a reduction in mobility. These parameters were differentially modified by the high as compared to the low dose of naloxone. Two days following implantation of pumps delivering the high dose of naloxone, the hyperalgesia of the inflamed paw was potentiated: by six days, this effect was lost. Further, one day after removal of pumps yielding the high dose, the inflamed paw showed a normalization of thresholds, that is a "rebound antinociception". One day later, this effect had subsided. In distinction, at no time did the low dose of naloxone modify nociceptive thresholds. The high dose of naloxone enhanced the reduction in body weight and food intake shown by unilaterally inflamed rats whereas the low dose was ineffective. Neither dose affected the reduction in water intake or hypothermia of unilaterally inflamed animals. The high dose of naloxone reduced the mobility of unilaterally inflamed rats whereas the low dose was ineffective. Finally, by 10 days following pump removal, pathology had transferred to the contralateral paw. In rats which had received the high but not the low dose, this transfer was blocked. It is concluded that blockade of kappa-opioid receptors with a high dose of naloxone experts pronounced functional effects in unilaterally inflamed rats. In distinction, selective blockade of mu-receptors with a low dose is ineffective. The changes seen include not only an enhancement of the hyperalgesia of the inflamed tissue, but also an exacerbation of variables (body weight, food intake and motility) which reflect pain states.(ABSTRACT TRUNCATED AT 400 WORDS)

Rats were subcutaneously implanted with minipumps delivering naloxone (3.0 mg/kg/h) or distilled water. One day later, they were inoculated in the plantar surface of the right hind paw with Mycobacterium butyricum. Naloxone blocked the antinociceptive action of the mu-agonist, morphine, and the kappa-agonist, U69,593, and led to a sustained reduction in food and water intake. Thus, opioid receptors were effectively occupied. Rats receiving naloxone showed significantly less hindlimb swelling on days 2 and 3 post-implantation. On day 2 but not 5 post-implantation, the hyperalgesic response of the inoculated paw to noxious pressure was potentiated in rats receiving naloxone. At six days post-implantation, pumps were removed. Ten days after removal, the inflammation and hyperalgesia had spread to the contralateral hindlimb and to the forelimbs. The degree of this transfer was less pronounced in rats which had been receiving naloxone. These data suggest that opioids, via kappa-receptors, play a role in the control of nociception under inflammatory pain: however, this role may not be indispensable. Further, the processes governing the development and spread of inflammatory disease may be modulated by opioid mechanisms.

The experiments described here were aimed at further validating adjuvant arthritis as an animal model of chronic pain. It was found that the relative oral intake of a 0.008 mg/ml solution of fentanyl was higher in arthritic than in normal control rats; this difference was predicted by the notion that the analgesic effect of a substance may reinforce its intake in animals exposed to pain, more so than in normal pain-free animals. It was also found that body weight decreases and that vocalizations of aggregated rats increase as a result of the challenge; these effects suggest that the vegetative signs and the behavioral irritability which are characteristic of chronic pain in humans, also occur in arthritic animals. The pain which thus seems to be associated with adjuvant arthritis was estimated to have its onset on days 10-11, to peak on days 18-21, and to terminate on days 35-40 after inoculation with Mycobacterium butyricum.

Inoculation of rats at the tail-base with Mycobacterium led to arthritic swelling and inflammation of all four limbs. Immunoreactive (ir)-dynorphin (DYN) increased in anterior but not neurointermediate pituitary. In the brain, only thalamus showed a rise and, in spinal cord, a large elevation was seen. Ir-vasopressin (VP) was not affected in these tissues but increased in midbrain. These effects might reflect a role of DYN in the control of chronic pain. In addition, they support a differential modulation of DYN as compared to VP extrinsic to the hypothalamic-neurohypophyseal axis.

Inoculation of the tail base of rats with Mycobacterium butyricum led to an arthritic swelling and inflammation of the limbs which displayed a hyperalgesia to noxious pressure: these effects peaked at 3 weeks postinoculation. In vitro autoradiography of coronal sections of rat brain was used for a parallel determination of binding to mu-, delta- and kappa-opioid binding sites. In only two regions, the dorsomedial and dorsolateral parts of the periaqueductal grey (PAG), was a significant change seen: this comprised an increase in binding to kappa-sites, whereas mu- and delta-sites therein were unaffected. This region was analysed for opioid peptides derived from each of the three opioid peptide families known. While no change was seen in levels of immunoreactive (ir)-dynorphin1-17 A (DYN) and ir-Met-enkephalin, a decrease was detected in those of ir-beta-endorphin (beta-EP): this change was restricted to the PAG. These data demonstrate a highly localized and selective influence of chronic arthritic pain upon multiple opioid systems in the PAG of the rat, a structure playing a key role in the control of pain and in the expression of the antinociceptive actions of opioids. The data suggest a possible significance of PAG pools of beta-EP and kappa-receptors in the response to and modulation of chronic pain.

The paper reviews evidence that adjuvant arthritis in the rat is associated with chronic pain and discusses the time course and measurement of this putative pain. The available evidence is consistent with the view that arthritic rats suffer pain, but it appears difficult to formally establish the occurrence of chronic pain in animals. The data suggest the pain to be severe during weeks 2 and 3 and to persist during weeks 4 and 5 after inoculation. The continuing inflammation of joints likely results in movement-induced acutely elicited pains that may persist till about the 8th week. The severe pain during weeks 2 and 3 may be associated with a depression of some drives, and the entire week 2-8 period is likely associated with varying levels of chronic stress. Neurochemical and neurophysiological studies indicate that adjuvant arthritis profoundly influences several of the neurotransmission and neuroendocrine functions of brain and spinal cord; among the affected systems are substance P-ergic, serotonergic and endorphinergic systems. Adjuvant arthritis in the rat constitutes the only laboratory animal model of chronic pain that has been validated to a significant extent. It is suggested that the model be examined further and that additional animal models of chronic pain be developed.

Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study determined the time course of the ventilatory response to adjuvant arthritis in the rat. It was found that the minute ventilation of arthritic rats reliably exceeded that of control animals during a period of about 4 weeks. The ventilatory response had its onset during the 2nd week after inoculation of Mycobacterium butyricum in the tail base, peaked on day 21, and was statistically reliable up to the 35th day. A smaller difference persisted throughout the further six weeks of the study, which covered 77 days in all. The changes in minute ventilation appeared to be closely time-locked with the changes in body weight and paw diameter which are characteristic of rats with adjuvant arthritis. The peak minute ventilation of individual animals also correlated in a significant manner with changes in weight and in paw diameter. The data are consistent with an earlier attempt to characterize the time course of the chronic pain which is presumably associated with adjuvant arthritis in the rat; minute ventilation is discussed as a possible measure of this putative pain.

This study examined whether pain or stress can enhance the analgesic effects of spinally administered opiates. The experiments determined the effects of mechanically produced pain and of the stress of being restrained on the analgesic effects of 0.63 microgram of epidural sufentanil in rats using a tail-withdrawal procedure. The painful, as well as the stressful, conditions appeared to increase the duration of opiate analgesia 3.7- and 3.0-fold, respectively. The data offer initial evidence that pain and other stressful conditions can enhance the analgesia produced by spinally administered opiates.

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)