Pain, sensory function, and neurogenic inflammatory response in young women with low mood.

OBJECTIVE: To determine the relationship of mood status to pain complaints, sensory function, neurogenic inflammatory response, and general health in young women. METHODS: Ninety-three women aged 18-29 participated in the study and were categorized by SCL-90-R depression score into low-mood (n=21) and normal-mood (n=72) groups. All subjects were below the threshold for possible clinical depression. RESULTS: Low mood was associated with decreased tactile sensitivity, reduced response to topical capsaicin, and increased complaints of back, joint, muscle, and visceral pain, but not headache, when compared to normal mood controls. Low mood was also associated with reported poorer health and physical functioning, increased psychopathology, and family history of mood problems. CONCLUSION: These data show that even subclinical low mood is associated with marked alterations in health and psychophysiological function.

Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test.

The present study investigated the effect of acute systemic administration of six progesterone metabolites on formalin-induced pain in the rat. The 3alpha-hydroxylated metabolites allopregnanolone and pregnanolone are highly potent positive modulators at the GABA(A) receptor and produced a biphasic effect on pain in the formalin test. Dose-dependent antinociception was observed at lower doses (maximal antinociception at 0.16mg/kg) and was reversed at higher doses. Bicuculline abolished the antinociceptive effect. The 3beta-hydroxylated epipregnanolone and isopregnanolone are inactive or only weekly active at the GABA(A) receptor, and did not affect formalin-induced pain. 5alpha- and 5beta-dihydroprogesterone have also been shown to have low affinity for the GABA(A) receptor, but can be rapidly metabolized to their 3alpha-hydroxylated counterparts. In the formalin test, they produced a biphasic effect on pain similar to that of pregnanolone and allopregnanolone, but with lower potency. The effect was reversible by bicuculline, showing involvement of the GABA(A) receptor, and was blocked by indomethacin, implying that the antinociceptive effect is dependent on their conversion to allopregnanolone or pregnanolone. The results indicate that GABA-ergic progesterone metabolites modulate nociception. A change in levels of GABA-ergic progesterone metabolites, such as is observed in depression, chronic fatigue and premenstrual dysphoric disorder could, therefore, contribute to the pain complaints associated with these disorders.

Vestibular tactile and pain thresholds in women with vulvar vestibulitis syndrome.

Vulvar vestibulitis syndrome (VVS) is a common cause of dyspareunia in pre-menopausal women. Little is known about sensory function in the vulvar vestibule, despite Kinsey's assertion that it is important for sexual sensation. We examined punctate tactile and pain thresholds to modified von Frey filaments in the genital region of women with VVS and age- and contraceptive-matched pain-free controls. Women with VVS had lower tactile and pain thresholds around the vulvar vestibule and on the labium minus than controls, and these results were reliable over time. Women with VVS also had lower tactile, punctate pain, and pressure-pain tolerance over the deltoid muscle on the upper arm, suggesting that generalized systemic hypersensitivity may contribute to VVS in some women. In testing tactile thresholds, 20% of trials were blank, and there was no group difference in the false positive rate, indicating that response bias cannot account for the lower thresholds. Women with VVS reported significantly more catastrophizing thoughts related to intercourse pain, but there was no difference between groups in catastrophizing for unrelated pains. Pain intensity ratings for stimuli above the pain threshold increased in a parallel fashion with log stimulus intensity in both groups, but the ratings of distress were substantially greater in the VVS group than in controls at equivalent levels of pain intensity. The data imply that VVS may reflect a specific pathological process in the vestibular region, superimposed on systemic hypersensitivity to tactile and pain stimuli.

The formalin test in the mouse: a parametric analysis of scoring properties.

We investigated the scoring properties of the mouse formalin test using the time-sampling method recently developed for infant and adult rats. Formalin was injected under the plantar surface of one rear paw (10 microl, 1-8%), and pain behaviours (paw favouring, lifting and licking) and behavioural state were recorded. Correlational and regression analyses indicated that scores composed of combinations of all three pain behaviours, either summed or weighted, provided less variable indices of pain than licking alone. The maximum percent effect (MPE(50); i.e. pain behaviour 50% of the time) for the log formalin concentration-effect curves was 3-4% in both phases. Habituation to the test environment prior to testing did not alter the MPE(50)s, but slopes were lower in unhabituated mice, dramatically increasing the size of the confidence interval. Formalin dose-dependently reduced locomotion, rearing and sniffing in both the first phase and the early part of the second phase. The combination measures were sensitive to morphine (2-8 mg/kg), amphetamine (1-4 mg/kg), dipyrone (50-200 mg/kg), xylazine (0.25-1 mg/kg), and acepromazine (0.25-1 mg/kg), and resistant to diazepam (0.5-2 mg/kg), pimozide (0.05-0.25 mg/kg), pentobarbital (10 and 15 mg/kg) and indomethacin (2-8 mg/kg). Decreased pain was correlated with increased motor activity for morphine and amphetamine, and with decreased activity for xylazine and acepromazine; dipyrone and indomethacin did not alter activity levels.

Improving the efficiency of the formalin test.

A time-sampling method that allows up to eight rats to be tested simultaneously in the formalin test is described and compared to the continuous rating method. Time sampling the behavioural response to formalin every 1 or 2 min produces scores that are essentially identical to continuous rating for both the formalin concentration effect relationship and the morphine dose effect relationship, with no loss of statistical power. The most important advantage of the method is that it allows data on other aspects of the rats' behaviour, such as behavioural state and the side effects of drugs to be scored during the formalin test. Formalin injection produces a dose-dependent decrease in locomotor and exploratory activity. The activity pattern of rats is normalized at morphine doses that produce about a 50% reduction in pain, while morphine doses high enough to completely suppress the pain response are accompanied by considerable sedation. The use of the jackknifing procedure to obtain unbiased estimates of the variability of parameters estimated from dose effect relationships is also described.

The formalin test: a dose-response analysis at three developmental stages.

We investigated the behavioral response of rat pups to intraplantar injection of varying formalin concentrations using a time-sampling method. At 3 days of age, the response was monophasic and persisted for the whole hour, even at low formalin concentrations. Flexion, shaking and licking the injected limb and hind-limb kicking correlated strongly with log formalin concentration (r = 0.82); behavioral state was altered only at the highest concentration. The response on day 15 was also monophasic, but it waned in 30 min, even at the highest formalin concentration tested. Flexion, shaking and licking of the injected limb were strong pain measures (r = 0.83). The response at 25 days was biphasic, and the adult measures, paw lifting and licking, produced a good formalin concentration-effect relationship (r = 0.80). The log concentration-effect relationships for formalin at the three developmental stages and for adult rats were parallel, but between 3 days and 15 days of age, the relationship shifted to the right by 2.5-fold, and by a further 4-fold between 15 and 25 days, when the sensitivity to formalin-induced pain was similar to that in adults. The data describe efficient, quantitative measures of formalin-induced pain for developing rats, show that the pain response is log-linearly related to formalin concentration throughout development, and demonstrate that the sensitivity to formalin-induced pain is about 10-fold higher in neonatal rats than in weanlings. the data imply that there are major qualitative changes in pain processing as the nervous system develops.

The effect of lesions of the dorsolateral funiculus on formalin pain and morphine analgesia: a dose-response analysis.

There has been conflicting evidence concerning the role of descending bulbospinal influences on pain and opioid analgesia in the formalin test. We examined the effect of lesions of the dorsolateral funiculus (DLF) on dose-effect relations for formalin and morphine in the formalin test. Experiment 1 showed that DLF lesions reduced the effect of 5 mg/kg morphine on pain in the tail-flick test, and eliminated morphine's effect on pain produced by 2.5% formalin. When lower concentrations of formalin were used, DLF lesions produced hyperalgesia, indicated by a left shift 1.7-fold) of the formalin concentration-response curve. In experiment 2, DLF lesions increased the pain produced by 1.25% formalin and shifted the dose-response relation for the effect of morphine on the second phase of the pain response produced by 1.25% formalin to 2.5-fold higher doses. The data show that DLF lesions increase sensitivity to the pain-inducing effect of formalin, and this accounts for a substantial component of the effect of DLF lesions on morphine analgesia.

Effects of morphine, pentobarbital and amphetamine on formalin-induced behaviours in infant rats: sedation versus specific suppression of pain.

The behavioural response of infant rats to intraplantar injection of formalin consists of specific directed behaviours (limb flexion, shaking and licking the injected paw) and non-specific behaviours that are also induced by non-nociceptive stimulation (squirming, hind limb kicks and whole body jerks), with specific indicators becoming more frequent as pups mature. The present study examined the effects of systemic morphine, pentobarbital and D-amphetamine on formalin-induced behaviours and behavioural state in rat pups from 1 to 20 days of age. Morphine (1 mg/kg) almost completely suppressed both specific and non-specific indicators of pain, and produced mild sedation relative to handled control pups. Pentobarbital (10 mg/kg) produced a similar degree of sedation and suppression of non-specific measures as morphine, but only had weak effects on specific measures in pups less than 1 week old, and no effects thereafter. Suppression of both specific and non-specific pain measures after amphetamine (2 mg/kg) emerged during the 2nd week of life and was not associated with sedation. Thus, morphine produced behavioural analgesia in infant rats in a model of injury-induced inflammatory pain from the 1st postnatal day, when their neurological maturity is similar to a 25-week human fetus, and 1 week before antinociception is observed in thermal and pressure tests. The effects of morphine were qualitatively different from a sedative dose of pentobarbital. The data support the contention that opioids have specific analgesic effects in premature human neonates and underline the need for pain measures that discriminate between sedation and analgesia.

The formalin test: scoring properties of the first and second phases of the pain response in rats.

The formalin test is increasingly used as a model of injury-produced pain but there is no generally accepted method of pain rating. To examine the properties of various pain rating methods we established dose-response relations for formalin injected in the plantar surface of one hind paw, and the analgesic effects of morphine and amphetamine using the most frequently reported behavioural measures of pain (favouring, lifting, licking and flinching/shaking of the injured paw) and combinations of these. Licking, elevation and favouring of the injected paw showed a biphasic response at all formalin doses. Flinching varied in form across the time course of formalin, and the biphasic nature of the behaviour was not as apparent. In untreated rats all these behaviours were infrequent. Flinching and favouring were increased after injection of local anaesthetic into the paw but remained negligible relative to the effect of formalin. Grooming other than that directed to the injected paw was elevated in a dose-dependent manner by formalin. Intercorrelations between the behaviours were different for the initial response and the second phase. Correlational analysis indicated that no single behavioural measure was a strong predictor of formalin, morphine and amphetamine dose. A simple sum of time spent licking plus elevating the paw, or the weighted pain score of Dubuisson and Dennis (1977), were superior to any single measure (r ranging from 0.75 to 0.86). Addition of flinching and favouring to the combined pain score using multiple regression did not increase variance explained. Depending on the measure used, a sedative dose of pentobarbital produced apparent analgesia, hyperalgesia or no effect. The interphase depression of pain, as well as the analgesic effects of morphine and amphetamine, were all associated with increased motor activation. Power analysis indicated that using a moderate dose of formalin and a combined pain score gave the greatest power to detect differences in pain. It was also found that pain scores increase with ambient temperature and that rat strains may differ in formalin pain sensitivity.

The behavioral response to formalin in preweanling rats.

The behavioural response of rat pups, 1-20 days of age, to subcutaneous injection of formalin in a rear paw is described. Formalin-injected pups were compared to handled controls and to pups that received an injection of normal saline. Ongoing behaviour was recorded every 2 min for 60 min after injection. Injection of normal saline produced little disorganization of behaviour, although day-1, -3 and -6 pups did frequently flex the limb on the injected side early in the session. Injection of 10 microliters of 1% formalin depressed active and quiet sleep in pups 10 days old and younger. Much less disruption of sleep was observed in day-15 pups, and in day-20 pups it was necessary to increase the concentration of formalin to 2.5% to produce a consistent behavioural response. The specific responses of pups to formalin injection were flexion of the limb, shaking the limb, and licking the injected paw. Pups of all ages displayed all of these responses, but in pups younger than 10 days, only limb flexion was consistent. Shaking became a consistent response in day-10 pups and licking in day-15 and -20 pups. Non-specific behaviours (squirming, vigorous rear kicks with both hind limbs and convulsive whole body jerks) were markedly increased by formalin in younger pups with a developmental pattern: squirming and kicking in day-1 pups, kicking and jerking in day-3 to -15 pups. Non-specific behaviours decreased and specific behaviours increased with age. In addition, the overall intensity and duration of the response decreased with age. The biphasic time course of the response of adult rats to formalin injection did not appear until 15 days of age.

The prevalence of pain in hospitalized patients and resolution over six months.

Pain was assessed in 2415 randomly selected hospitalized patients. Fifty percent of the sample reported pain at the time of the interview, and 67% had experienced pain during the past 24 h. High levels of pain were more frequent in postpartum women, patients with diseases of the musculoskeletal systems and after injury or poisoning, but in all diagnostic categories there were patients whose lowest pain level in the preceding 24 h was moderate or severe. Patients who had undergone a surgical procedure during the past 7 days were more likely to report moderate or severe pain, but 21% of non-surgical patients reported moderate or severe pain. Twenty percent of those with pain reported that it had existed for more than 6 months. Patients reported significant impairment of function and distress as a consequence of pain. Use of analgesic medications was low overall and even lower for non-surgical patients. A decrease in pain over 3 weeks was predicted by pain of shorter duration, a shorter duration of hospitalization in the past year, and if a surgical procedure had been performed. None of these variables predicted pain resolution between 3 weeks and 3 or 6 months. Impairment of function did not increase with continuing pain but distress did. Medication use remained low at follow-up. The data indicate that current strategies to improve pain management need to be critically reviewed.

Pain on a surgical ward: a survey of the duration and intensity of pain and the effectiveness of medication.

The effectiveness of analgesic medication for post-surgical pain was surveyed in a surgical ward of a large general hospital. Since earlier studies have shown that pain generally decreases rapidly and is negligible by the fourth day after surgery, the patients in the survey were assigned to 2 groups: those given analgesics during the first 4 days after surgery, and those given analgesics for pain after the fourth day. The results show that the patients with pain that persists beyond day 4 comprise a substantial proportion of the patients in a surgery ward (31%), are older, tend to use more words to describe their pain, and are helped less by their prescribed analgesic medications. This group is prescribed lower doses of analgesics and receives them more frequently; however, this prescription strategy appears to be ineffective since 26% of these patients report increased pain after medication compared to only 2% in the group that received analgesics during the first 4 days.

Effects of peripheral antisympathetic treatments in the tail-flick, formalin and autotomy tests.

The effects of peripheral adrenergic depleting agents on the threshold for non-damaging heat pain (tail-flick test), inflammatory pain associated with tissue injury (formalin test), and chronic pain or dysaesthesia associated with nerve lesions (autotomy test) were examined. Tail-flick latencies were increased by agents which deplete peripheral adrenergic transmitters--6-hydroxydopamine (6-OHDA) and guanethidine--as well as by an agent which prevents the synthesis of noradrenaline--FLA63. A combination of guanethidine and FLA63 also increased latencies, but no more than either treatment alone. Formalin pain scores were reduced by FLA63+ guanethidine and 6-OHDA, but not by guanethidine or FLA63 alone. The percentage of rats that exhibited autotomy was reduced minimally by 6-OHDA and guanethidine treatments which started the day of surgery, maximally by guanethidine treatments which started 4 days before surgery, and not at all by guanethidine treatments which started 4 days after surgery. The results obtained in the formalin and autotomy tests are interpreted in terms of the possible roles of adrenergic transmitters in stimulating and sensitizing damaged afferents immediately after injury. The tail-flick results, however, suggest that adrenergic transmitters also act in lowering thresholds of normal peripheral receptor-fibre units. The relevance of the findings to the development of chronic pain are discussed.