Factors influencing the altered pain perception in the spontaneously hypertensive rat

Recent studies have demonstrated a hypoalgesia in hypertensive subjects. This study reports and evaluates factors responsible for the expression of the hypoalgesic behavior demonstrated by genetically hypertensive rats of the Okamoto-Aoki strain (SHR) as compared to normotensive age-matched Wistar-Kyoto rats (WKY). Analgesiometric assays were conducted by the hot plate method. SHR's hypoalgesic behavior was reversed by subcutaneously administered naloxone. The intravenous administration of naloxone did not alter arterial pressure or heart rate in either SHR or WKY. Subcutaneous administration of the peripherally acting ganglionic blocker hexamethonium bromide at a dose which lowered mean arterial blood pressure and thus decreased tonic baroreceptor stimulation, concomitantly reversed the SHR hypoalgesic behavior and induced a hyperalgesia in WKY. Denervation of the sino-aortic baroreceptors failed to alter the hypoalgesic behavior demonstrated by SHR. Denervation of the right vagal nerve trunk with associated cardiopulmonary baroreceptor afferents resulted in a reduction of the SHR hypoalgesic behavior and produced a hyperalgesic behavior in WKY as compared to age-matched sham operated controls over a 4 week period. These data suggest a possible physiological role for vagal afferent systems in the concomitant regulation of resting arterial blood pressure and responsiveness to aversive environmental stimuli. A discussion of the interaction between blood pressure and pain regulatory systems as potential substrates associated with the onset and maintenance of hypertension is provided.     

Biphasic alteration in the trigeminal nociceptive neuronal responses after intracerebroventricular injection of prostaglandin E2 in rats

To investigate the role of prostaglandin E₂ (PGE₂) in the brain in nociception electrophysiologically, we injected PGE₂ (0.1 fmol–1 nmol) into the lateral cerebroventricle (LCV) of anesthetized rats and observed the changes of the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The LCV injection of PGE₂ at 1 fmol and 10 fmol enhanced the responses of the majority of WDR neurons to noxious stimuli, whereas that of PGE₂ at 100 pmol and 1 nmol suppressed them. The enhancement and suppression of the nociceptive responses of WDR neurons were observed 15–25 min and 5–15 min after injection of PGE₂ at 10 fmol (3.53 pg) and 1 nmol (353 ng), respectively. On the other hand, the LCV injection of PGE₂ at both 10 fmol and 1 nmol had no effect on the responses of the low threshold mechanoreceptive neurons to skin brushing. These results provide electrophysiological evidence that brain-derived PGE₂ has biphasic effects on nociception, i.e., it induces mechanical hyperalgesia at lower doses and hypoalgesia at higher doses in rats.     

Swearing as a Response to Pain—Effect of Daily Swearing Frequency

Previously we showed that swearing produces a pain lessening (hypoalgesic) effect for many people.²⁰ This paper assesses whether habituation to swearing occurs such that people who swear more frequently in daily life show a lesser pain tolerance effect of swearing, compared with people who swear less frequently. Pain outcomes were assessed in participants asked to repeat a swear word versus a nonswear word. Additionally, sex differences and the roles of pain catastrophizing, fear of pain, and daily swearing frequency were explored. Swearing increased pain tolerance and heart rate compared with not swearing. Moreover, the higher the daily swearing frequency, the less was the benefit for pain tolerance when swearing, compared with when not swearing. This paper shows apparent habituation related to daily swearing frequency, consistent with our theory that the underlying mechanism by which swearing increases pain tolerance is the provocation of an emotional response.

Perspective

This article presents further evidence that, for many people, swearing (cursing) provides readily available and effective relief from pain. However, overuse of swearing in everyday situations lessens its effectiveness as a short-term intervention to reduce pain.     

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.     

Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats

AIM: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. METHODS: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. RESULTS: JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. CONCLUSIONS: These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.     

Aversive event unpredictability causes stress‐induced hypoalgesia

Temporal predictability, or knowing when a noxious stimulus will occur, has been implicated in stress‐induced hypoalgesia, but the contribution of event predictability, or knowing what the stimulus will be, remains poorly understood. To address this issue, we examined the effects of event predictability on pain intensity ratings and nociceptive flexion reflex responses. Participants repeatedly experienced five intensities of electrocutaneous stimulation, ranging from nonpainful to extremely painful, delivered either randomly (unpredictability group) or blocked (predictability group) with no cues provided. Unpredictable shocks produced the lowest pain ratings while evoking the highest flexion reflex responses. Moreover, anticipatory heart rate data indicated that unpredictable trials were the most physiologically arousing. Our findings show that uncertainty about the upcoming stimulus intensity is stressful and unpleasant, thereby causing hypoalgesia and reflex potentiation.     

Isometric exercise and pain in patellar tendinopathy: A randomized crossover trial

ObjectivesThe aim of this study was to compare the acute effects of isometric versus dynamic resistance exercise on pain during a pain-provoking activity, and exercise-induced hypoalgesia in participants with patellar tendinopathy.DesignThis study was a pre-registered randomised crossover study. Participants were blinded to the study hypothesis.MethodsParticipants (N = 21) performed a single session of high load isometric resistance exercise or dynamic resistance exercise, in a randomised order separated by a 7-day washout period. Outcomes were assessed before, immediately after, and 45 min post-exercise. The primary outcome was pain intensity scored on a numeric pain rating scale (NRS; 0–10) during a pain-provoking single leg decline squat (SLDS). Secondary outcomes were pressure pain thresholds (PPTs) locally, distally and remotely, as well as tendon thickness.ResultsThere was a significant decrease in pain NRS scores (mean reduction 0.9, NRS 95%CI 0.1–1.7; p = 0.028), and increase in PPTs at the tibialis anterior muscle (mean increase 34 kPa 95%CI 9.5–58.5; p = 0.009) immediately post-exercise. These were not sustained 45 min post-exercise for pain (NRS) or PPTs (p > 0.05). There were no differences between exercise on any outcome.ConclusionsWhile patients with patellar tendinopathy decreased pain during SLDS in response to resistance training, but the magnitude was small. Contraction mode may not be the most important factor in determining the magnitude of pain relieving effects. Similarly, there were only small increases in PPTs at the tibialis anterior which were not superior for isometric exercise.     

Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans

Pain inhibitory mechanisms are often assessed by paradigms of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM). In this study it was hypothesized that the spatial and temporal manifestations of EIH and CPM were comparable. The participants were 80 healthy subjects (40 females), between 18 and 65 years of age in this randomized, repeated-measures cross-over trial that involved data collection on 2 different days. CPM was assessed by 2 different cold pressor tests (hand and foot). EIH was assessed by 2 intensities of aerobic bicycling exercises and 2 intensities of isometric muscle contraction exercises (arm and leg). Pressure pain thresholds (PPTs) were recorded before, during, after, and 15 minutes after conditioning/exercise at sites local to and remote from the extremity used for cold pressor stimulation and exercise. PPTs increased at local as well as at remote sites during both cold pressor tests and after all of the exercise conditions except low-intensity bicycling. EIH after bicycling was higher in women than in men. CPM and the EIH responses after isometric exercises were comparable in men and women and were not affected by age. The EIH response was larger in the exercising body part compared with nonexercising body parts for all exercise conditions. High-intensity exercise produced greater EIH responses than did low-intensity exercise. The change in PPTs during cold pressor tests and the change in PPTs after exercises were not correlated. The CPM response was not dominated by local manifestations, and the effect was seen only during the stimulation, whereas exercise had larger local manifestations, and the effects were also found after exercise.     

Clonidine and yohimbine modulate the effects of naloxone on novelty-induced hypoalgesia

Previous research has shown that repeated daily pretreatment with the opiate receptor blocker naloxone retards the development of habituation to novelty-induced hypoalgesia. The present experiments were conducted in order to determine whether noradrenergic substrates mediate this effect. Animals in the NAL condition were administered 10 mg/kg naloxone prior to assessment of pain sensitivity on a 48.5° C hot plate. Control animals (SAL condition) were administered saline prior to pain assessment, and naloxone 2–4 h later. Paw lick latencies declined over repeated tests in SAL animals, suggesting the habituation of novelty hypoalgesia. Naloxone pretreatment attenuated this decline. The longer paw lick latencies observed in NAL condition animals were reduced by administration of 2 µg/kg clonidine, a specific noradrenergic alpha-2 receptor agonist, and enhanced in a dose dependent (0.5–4.0 mg/kg) fashion by the alpha-2 antagonist yohimbine. Clonidine and yohimbine either failed to alter pain reactivity in control animals, or produced less marked effects than those observed in naloxone-exposed animals. These results suggest that noradrenergic substrates mediate naloxone's effects on novelty hypoalgesia.