Acute Mechanical Hyperalgesia Research Articles

Contact hypersensitivity to oxazolone provokes vulvar mechanical hyperalgesia in mice (P6028)

Abstract Vulvodynia can affect ~20% of women of child-bearing age. Activities such as contact with tight clothing or sexual intercourse provoke burning pain sensations whose etiology and underlying mechanisms are poorly understood. Epidemiological evidence suggests a link between a history of environmental allergies and the risk of developing vulvodynia. Clinicians find increased mast cell numbers, hyperinnervation and up-regulation of inflammatory cytokines in biopsies from vulvodynia patients vs. controls. An allergy-based mast cell focused mouse model of vulvodynia is needed to elucidate the mechanisms underlying this pathology. We show that challenge with contact hypersensitivity allergen oxazolone produces acute mechanical hyperalgesia in the vulvar region of previously sensitized female mice. Acute pain is localized to the challenge site, lasts up to 24 hours post-challenge and is accompanied by influx of neutrophils into the labiar tissue and up-regulation of several inflammatory cytokine genes including IL-6, Cxcl-1 and Cxcl-2. Pre-challenge administration of H1R-antagonist pyrilamine, tricyclic antidepressant amitryptiline, and sodium cromoglycate all abrogate the hyperalgesic response. Our findings provide the first evidence of the induction of measurable pain following an allergic response in the labiar/vulvar tissue in mice thus establishing a model that can be adapted to chronic challenges and long-term assessment of pain with and without ongoing inflammation.

Eccentric exercise induces chronic alterations in musculoskeletal nociception in the rat

Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate the mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, which returned to baseline at 120 h post-exercise. When nociceptive thresholds had returned to baseline, intramuscular injection of prostaglandin E(2) (PGE(2) ) induced hyperalgesia that was unattenuated 240 h later, much longer than PGE(2) -induced hyperalgesia in unexercised rats (4 h). This marked prolongation of PGE(2) hyperalgesia induced by eccentric exercise was prevented by the spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE(2) hyperalgesia were inhibited by the spinal intrathecal administration of antisense for the interleukin-6 but not the tumor necrosis factor α type 1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, and suggest novel approaches for the prevention and treatment of exercise- or work-related chronic musculoskeletal pain syndromes.

Hyperalgesic priming is restricted to isolectin B4-positive nociceptors

We have previously described a rat model for the contribution of neuroplastic changes in nociceptors to the transition from acute to chronic pain. In this model a prior injury activates protein kinase C epsilon (PKCε), inducing a chronic state characterized by marked prolongation of the hyperalgesia induced by inflammatory cytokines, prototypically prostaglandin E 2 (PGE 2), referred to as hyperalgesic priming. In this study we evaluated the population of nociceptors involved in priming, by lesioning isolectin B4-positive (IB4(+)) nociceptors with intrathecal administration of a selective neurotoxin, IB4-saporin. To confirm that the remaining, TrkA(+)/IB4(−), nociceptors are still functional, we evaluated if nerve growth factor (NGF) induced hyperalgesia. While pretreatment with IB4-saporin eliminated the acute mechanical hyperalgesia induced by glia-derived neurotrophic factor (GDNF), NGF and ΨεRACK, a highly selective activator of PKCε, induced robust hyperalgesia. After injection of NGF, GDNF or ΨεRACK, at a time at which hyperalgesia induced by PGE 2 is markedly prolonged (hyperalgesic priming) in control rats, in IB4-saporin-pretreated rats PGE 2 failed to produce this prolonged hyperalgesia. Thus, while PKCε is present in most dorsal root ganglion neurons, where it can contribute to acute mechanical hyperalgesia, priming is restricted to IB4(+)-nociceptors, including those that are TrkA(+). While PKCε activation can induce acute hyperalgesia in the IB4(+) population, it fails to induce priming. We suggest that hyperalgesic priming occurs only in IB4(+) nociceptors, and that in the peripheral terminals of nociceptors separate intracellular pools of PKCε mediate nociceptor sensitization and the induction of hyperalgesic priming.

Mechanisms Mediating Vibration-Induced Chronic Musculoskeletal Pain Analyzed in the Rat

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome.

Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: Critical period and dependence on initial afferent activity

Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury-related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. Plantar hindpaw incision produces acute mechanical hyperalgesia in neonatal and adult rats, but incision in neonatal pups has an additional effect on the response to subsequent injury. With initial incision at postnatal day (P) 3 or 6, the degree of hyperalgesia following repeat incision 2weeks later was greater than in animals having a single incision at the same age. At older ages (initial incision at P10, P21 or P40) responses did not differ in repeat and single incision groups. To test the role of primary afferent activity, levobupivacaine sciatic block was performed prior to P6 plantar incision, and controls received saline or subcutaneous levobupivacaine. Repeat peri-operative, but not a single pre-operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri-operative analgesia used for neonatal surgery.

Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice

We have shown that somatostatin released from activated capsaicin-sensitive nociceptive nerve endings during inflammatory processes elicits systemic anti-inflammatory and analgesic effects. With the help of somatostatin receptor subtype 4 gene-deleted mice (sst(4)(-/-)), we provide here several lines of evidence that this receptor has a protective role in a variety of inflammatory disease models; several symptoms are more severe in the sst(4) knockout animals than in their wild-type counterparts. Acute carrageenan-induced paw edema and mechanical hyperalgesia, inflammatory pain in the early phase of adjuvant-evoked chronic arthritis, and oxazolone-induced delayed-type hypersensitivity reaction in the skin are much greater in mice lacking the sst(4) receptor. Airway inflammation and consequent bronchial hyperreactivity elicited by intranasal lipopolysaccharide administration are also markedly enhanced in sst(4) knockouts, including increased perivascular/peribronchial edema, neutrophil/macrophage infiltration, mucus-producing goblet cell hyperplasia, myeloperoxidase activity, and IL-1beta, TNF-alpha, and IFN-gamma expression in the inflamed lung. It is concluded that during these inflammatory conditions the released somatostatin has pronounced counterregulatory effects through sst(4) receptor activation. Thus, this receptor is a promising novel target for developing anti-inflammatory, analgesic, and anti-asthmatic drugs.

Involvement of the transient receptor potential vanilloid 1 (TRPV1) in the development of acute visceral hyperalgesia during colorectal distension in rats

Transient receptor potential vanilloid 1 (TRPV1) channels have been implicated in pain mechanisms and, particularly, in the development of hyperalgesia. We used selective TRPV1 antagonists (NGV-1, SB-750364 and JYL 1421) to assess the role of TRPV1 channels in repetitive noxious colorectal distension (CRD)-induced visceral pain responses in rats. Isobaric CRD (80 mmHg) induced a viscerosomatic response, indicative of visceral pain associated to the distension procedure. Repetition (12 consecutive distensions) of the CRD resulted in an increase in the response over time (119 ± 23% increase at distension 12, P < 0.05 vs response during the 1st distension) indicative of acute mechanical sensitization. NGV-1 (0.1, 0.3, 1 or 3 μmol/kg, i.v.) prevented in a dose-related manner the development of sensitization, without inducing hypoalgesic responses. SB-750364 (30 μmol/kg, i.v.) had a transitory effect, partially reducing the sensitization response, while JYL 1421 (4.7 μmol/kg, i.v.) was without effect. In the same conditions, the cannabinoid receptor 1 (CB 1) agonist, WIN55,212-2 (0.1 μmol/kg) reduced pain responses leading to a hypoalgesic state. At 3 μmol/kg, NGV-1, did not affect the pressure–volume relationship during CRD, indicating that TRPV1 channels do not modulate colonic compliance. These observations suggest that TRPV1 channels are involved in the development of acute mechanical colonic hyperalgesia during repetitive noxious CRD in rats. Antagonism of TRPV1 channels might result in antihyperalgesic effects without hypoalgesic activity and might be beneficial in the treatment of visceral pain disorders, such as irritable bowel syndrome. These observations warrant the clinical assessment of TRPV1 antagonists for the treatment of visceral pain.

CB1Receptors Mediate the Analgesic Effects of Cannabinoids on Colorectal Distension-Induced Visceral Pain in Rodents

Activation of cannabinoid receptors (CB(1), CB(2) and GPR(55)) produces analgesic effects in several experimental pain models, including visceral pain arising from the gastrointestinal tract. We assessed the role of CB(1), CB(2), and GPR(55) receptors and the endogenous cannabinoid system on basal pain responses and acute mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of cannabinoid receptor agonists and antagonists on pain-related responses to CRD were assessed in rats and in wild-type and CB(1) receptor knock-out mice. The dual CB(1/2) agonist, WIN55,212-2, and the peripherally acting CB(1)-selective agonist, SAB-378, inhibited pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The analgesic effects of WIN55,212-2 and SAB-378 were blocked by the selective CB(1) antagonist SR141716, but were not affected by the selective CB(2) antagonist SR144528. SR141716, per se, increased the responses to repetitive noxious CRD, indicative of hyperalgesia, and induced pain-related responses during non-noxious CRD (20 mmHg), indicative of allodynia. The cannabinoid receptor agonists anandamide, virodhamine and O-1602 had no effect. At analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced analgesia, whereas SR141716 induced hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB(1)-knock-out mice. These data indicate that peripheral CB(1) receptors mediate the analgesic effects of cannabinoids on visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by SR141716 suggest the existence of an endogenous cannabinoid tone and the activation of CB(1) receptors during noxious CRD.

Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: A functional MRI study

One of the most distressing symptoms of many neuropathic pain syndromes is the enhanced pain sensation to tactile or thermal stimulation (hyperalgesia). In the present study we used functional magnetic resonance imaging (fMRI) and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human ultraviolet (UV)-B model. To investigate pharmacological modulation, we examined potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 min after a 5-min intravenous infusion of either saline (placebo), parecoxib 40 mg or ASA 1000 mg. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. Analgesic effects were found in primary (S1) and secondary (S2) somatosensory cortices, parietal association cortex (PA), insula, anterior parts of the cingulate cortex and prefrontal cortices. These brain areas were also modulated under antihyperalgesic conditions. However, we observed a greater drug-induced modulation of mainly PA and inferior frontal cortex during mechanical hyperalgesia; during acute mechanical pain there was a greater modulation of mainly bilateral S2. Therefore, the results of the present study suggest that there is a difference in the brain areas modulated by analgesia and antihyperalgesia.

Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study

One of the most distressing symptoms of many neuropathic pain syndromes is the enhanced pain sensation to tactile or thermal stimulation (hyperalgesia). In the present study we used functional magnetic resonance imaging (fMRI) and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human ultraviolet (UV)-B model. To investigate pharmacological modulation, we examined potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 min after a 5-min intravenous infusion of either saline (placebo), parecoxib 40 mg or ASA 1000 mg. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. Analgesic effects were found in primary (S1) and secondary (S2) somatosensory cortices, parietal association cortex (PA), insula, anterior parts of the cingulate cortex and prefrontal cortices. These brain areas were also modulated under antihyperalgesic conditions. However, we observed a greater drug-induced modulation of mainly PA and inferior frontal cortex during mechanical hyperalgesia; during acute mechanical pain there was a greater modulation of mainly bilateral S2. Therefore, the results of the present study suggest that there is a difference in the brain areas modulated by analgesia and antihyperalgesia.

PLC-β3 signals upstream of PKCε in acute and chronic inflammatory hyperalgesia

While protein kinase Cε has been shown to contribute to acute and chronic mechanical hyperalgesia, its upstream signaling pathway has received little attention. Since phospholipase C can signal to PKCε and has been implicated in nociceptor sensitization, we tested if it is upstream of PKCε in mechanisms underlying primary mechanical hyperalgesia. In the rat, the PKCε-dependent mechanical hyperalgesia and hyperalgesic priming (i.e., a form of chronic latent enhanced hyperalgesia) induced by carrageenan were attenuated by a non-selective PLC inhibitor U-73122. A lipid mediator of PLC signaling, l-α-lysophosphatidylcholine produced dose-dependent mechanical hyperalgesia and hyperalgesic priming, which was attenuated by EAVSLKPT, a selective PKCε inhibitor. However, U-73122 did not attenuate hyperalgesia induced by ψεRACK, a selective PKCε activator. Antisense to PLC-β3 isoform, which was found in small-diameter dorsal root ganglion neurons, also attenuated carrageenan-induced acute and chronic-latent hyperalgesia. These studies support the suggestion that PLC-β3 is an important upstream signaling molecule for PKCε-mediated acute and chronic inflammatory pain.

Brain imaging of analgesic and antihyperalgesic effects by cyclooxygenase inhibition in an experimental human pain model: a functional MRI-study

One of the most distressing symptoms of pain syndromes is the enhanced pain sensation (hyperalgesia). Understanding the pathophysiology of hyperalgesia and the mode of action of antihyperalgesic drugs will potentially lead to better strategies in neuropathic pain therapy. In the present study we used fMRI in combination with quantitative sensory testing and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human UV-B model. To gain insight into pharmacological modulation of pain and hyperalgesia, we investigated potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase (COX) inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers (mean age 27.4 years) participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 minutes after a 5 minutes lasting intravenous infusion of either saline (placebo), parecoxib 40mg or ASA 1000mg. During fMRI experiments, subjects were asked to rate the evoked pain sensations on a visual analogue scale. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. However, analgesic and antihyperalgesic drug effects differed substantially. Analgesic effects were found in primary and secondary somatosensory cortices and anterior parts of the cingulate gyrus. In contrast, antihyperalgesic effects were detected in primary somatosensory, parietal association and anterior cingulate cortex, but not in secondary somatosensory cortices. Therefore, we provide evidence for a differential modulation of brain areas under either analgesia and antihyperalgesia.

Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat.

Tumor necrosis factor alpha (TNF) injected into the sciatic nerve and neutralizing antibodies to its receptor injected around the nerve are respectively associated with inducing and blocking pain behavior beginning 1 to 3 days post-injection. This study examined the acute effects of TNF applied around the nerve trunk on the mechanical threshold (determined with von Frey hairs) and withdrawal latency to radiant heat. TNF (0.9 and 7.7 ng in 90 microL) injected onto the nerve via an indwelling catheter elicited a decrease in mechanical threshold. Following the low dose of TNF, no change in thermal latency was observed; after the 7.7 ng dose, thermal thresholds decreased and returned to baseline multiple times within the 3-hour observation period. Identical doses of TNF injected near, but not on the nerve, 90 ng of TNF injected on the nerve, and vehicle were without effect on either modality. These data indicate that effects of acutely administered TNF to the nerve trunk are capable of producing modality specific pain behavior. These changes may represent a first step in TNF-induced neuropathic pain.

Examination of the role of the cerebral cortex in the perception of pain using functional magnetic resonance imaging

In the following review we outline several of the unique difficulties associated with designing and interpreting functional imaging studies of pain perception. Unlike other sensory modalities, the cortical processing of pain is unique, as is the pain experience itself. Unlike other sensory systems, pain processing does not take place in one dedicated region of the cortex. Rather, nociceptive cells are sparsely distributed through the somatosensory cortex. Further, pain is singular in that it has both sensory-discriminative and affective-motivational components, which are probably subserved by different neuroanatomic substrates. Finally, abnormal pain sensation, such as neuropathic pain syndromes, may have different or additional mechanisms that require special consideration. We have illustrated these points with examples from our own work on acute pain and secondary mechanical hyperalgesia, and work from other laboratories.

Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat

The effects of inhibition of thalamic NMDA receptor function and synthesis on thermal and mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan in the rat were studied in the `acute' phase (within 3–5 h) and the `subacute' phase (24 h) after carrageenan administration. Blockade of NMDA receptors was produced by intrathalamic injection of d,2-amino-5-phosphonovaleric acid (D-APV) and NMDA receptor synthesis was decreased (or not) by pretreatment of rats with intrathalamic (hindlimb representation area) injections of antisense, sense or missense oligodeoxynucleotides (ODNs) directed against the NR1 subunit of the NMDA receptor complex. Treatment with D-APV, but not saline, in the contralateral (but not ipsilateral) thalamus significantly reduced both the acute thermal and mechanical hyperalgesia in the injected paw; these same rats demonstrated significantly less thermal and mechanical hyperalgesia in the sub-acute phase than rats that had received saline or D-APV in the ipsilateral thalamus. None of the treatments had any effect on withdrawal responses of the uninjected hindpaw. Rats pretreated with NR1 sense or missense ODNs developed both thermal and mechanical hyperalgesia that was equivalent in magnitude and duration to rats that received intrathalamic saline injections. In contrast, rats pretreated with NR1 antisense ODN did not develop either acute or subacute thermal hyperalgesia; they developed less mechanical hyperalgesia than saline, sense or missense ODN-treated rats. Antisense ODN-treated rats also displayed a decrease in the number of thalamic NMDA receptors as determined by receptor binding assay. These results suggest an involvement of thalamic NMDA receptors in the development and maintenance of hyperalgesia associated with neurogenic inflammation in a model of tonic pain.

Chapter 14 Acute mechanical hyperalgesia in the rat can be produced by coactivation of spinal ionotropic AMPA and metabotropic glutamate receptors, activation of phospholipase A2 and generation of cyclooxygenase products

Publisher Summary This chapter focuses on the characterization of the glutamate receptor subtypes and the signal transduction mechanisms that are involved in acute mechanical hyperalgesia. It discusses the results obtained from the experiment that acute mechanical hyperalgesia can be produced by coactivation of spinal ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and metabotropic glutamate receptor subtypes, activation of PLA, and production of cyclooxygenase (COX) products. Given the previous reports on thermal hyperalgesia, the results presented in the chapter are consistent with a role for spinal N-methyl-D-aspartate (NMDA) receptors, nitric oxides (NO), and protein kinase C (PKC) in thermal hyperalgesia and for coactivation of spinal AMPA and metabotropic glutamate receptors, activation of PLA, and production of COX products in mechanical hyperalgesia. Further, these data suggest that acute thermal and mechanical hyperalgesia rely principally on the activation of different signal transduction mechanisms in the spinal cord. The chapter examines the role of phospholipase C (PLC), which has been linked to the activation of the metabotropic receptor. However, as with NO and PKC inhibitors, it is found that the PLC inhibitor neomycin does not affect the acute mechanical hyperalgesia produced by coactivation of AMPA and metabotropic glutamate receptors.

Acute mechanical hyperalgesia is produced by coactivation of AMPA and metabotropic glutamate receptors.

Several recent reports document that activation of the NMDA receptor is required for the development and maintenance of thermal hyperalgesia. In contrast, the receptor subtype(s) involved in mechanisms that underlie mechanical hyperalgesia are at present unknown. We report here that acute mechanical hyperalgesia in the rat is not produced by NMDA receptor agonists, but instead requires coactivation of ionotropic AMPA and metabotropic glutamate receptor subtypes. Collectively, the results are consistent with a role for activation of spinal cord neurons using NMDA receptor agonists in mechanisms of thermal hyperalgesia and for coactivation of AMPA and metabotropic glutamate receptors on spinal cord neurons in mechanisms of mechanical hyperalgesia.