Reward deficiency and anti-reward in pain chronification.

Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification).

Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors.

Activation of the cAMP/protein kinase A (PKA) second messenger cascade has been implicated in the induction of mechanical hyperalgesia by inflammatory mediators. We examined the role of this cascade in mechanical sensitization of nociceptive neurons that innervate the meninges, a process thought to be involved in the pathophysiology of headache syndromes such as migraine. Single unit activity was recorded in the trigeminal ganglion from 40 mechanosensitive dural afferents (conduction velocitity: 0.3-6.6 m s(-1)) and nine mechanically insensitive dural afferents (MIAs) (conduction velocitity: 0.3-2.8 m s(-1)) while stimulating the dura with a servo force-controlled stimulator or von Frey monofilaments, respectively. Local application to the dura of dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP, 100 microM), a stable membrane-permeant cAMP analogue, produced mechanical sensitization in the majority of mechanosensitive units (19/29, 66 %). Two distinct patterns of mechanical sensitization were observed. Thirty-eight per cent of the units exhibited only a decrease in threshold (TH group), while 28 % showed only an increase in suprathreshold responses (STH group). dbcAMP also induced mechanosensitivity in the majority of MIA units (6/9, 67 %). dbcAMP-induced sensitization was blocked by the PKA inhibitors, Rp-cAMP (1 mM) and H-89 (100 microM). A mixture of inflammatory mediators induced both components of sensitization in the majority of mechanosensitive units tested. However, in each unit, PKA inhibitors blocked only one of the two effects (either TH or STH). Units that were classified as TH or STH also differed in their baseline stimulus-response slopes, thresholds and conduction velocities. These findings implicate the cAMP-PKA cascade in sensitization of dural mechanonociceptors and suggest that this cascade may produce sensitization through at least two different mechanisms operating in separate neuronal populations.

Electrophysiological evidence for tetrodotoxin-resistant sodium channels in slowly conducting dural sensory fibers.

A tetrodotoxin (TTX)-resistant sodium channel was recently identified that is expressed only in small diameter neurons of peripheral sensory ganglia. The peripheral axons of sensory neurons appear to lack this channel, but its presence has not been investigated in peripheral nerve endings, the site of sensory transduction in vivo. We investigated the effect of TTX on mechanoresponsiveness in nerve endings of sensory neurons that innervate the intracranial dura. Because the degree of TTX resistance of axonal branches could potentially be affected by factors other than channel subtype, the neurons were also tested for sensitivity to lidocaine, which blocks both TTX-sensitive and TTX-resistant sodium channels. Single-unit activity was recorded from dural afferent neurons in the trigeminal ganglion of urethan-anesthetized rats. Response thresholds to mechanical stimulation of the dura were determined with von Frey monofilaments while exposing the dura to progressively increasing concentrations of TTX or lidocaine. Neurons with slowly conducting axons were relatively resistant to TTX. Application of 1 microM TTX produced complete suppression of mechanoresponsiveness in all (11/11) fast A-delta units [conduction velocity (c.v.) 5-18 m/s] but only 50% (5/10) of slow A-delta units (1.5

Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons.

Chemical activation and sensitization of trigeminal primary afferent neurons innervating the intracranial meninges have been postulated as possible causes of certain headaches. This sensitization, however, cannot explain the extracranial hypersensitivity that often accompanies headache. The goal of this study was to test the hypothesis that chemical activation and sensitization of meningeal sensory neurons can lead to activation and sensitization of central trigeminal neurons that receive convergent input from the dura and skin. This hypothesis was investigated by recording changes in the responsiveness of 23 [16 wide-dynamic range (WDR), 5 high threshold (HT), and 2 low threshold (LT)] dura-sensitive neurons in nucleus caudalis to mechanical stimulation of their dural receptive fields and to mechanical and thermal stimulation of their cutaneous receptive fields after local application of inflammatory mediators or acidic agents to the dura. Responses to brief chemical stimulation were recorded in 70% of the neurons; most were short, lasting the duration of the stimulus only. Twenty minutes after chemical stimulation of the dura, the following changes occurred: 1) 95% of the neurons showed significant increases in sensitivity to mechanical indentation of the dura: their thresholds to dural indentation changed from 1.57 to 0.49 g (means, P < 0.0001), and the response magnitude to identical stimuli increased by two- to fourfold; 2) 80% of the neurons showed significant increases in cutaneous mechanosensitivity: their responses to brush and pressure increased 2.5- (P < 0.05) and 1. 6-fold (P < 0.05), respectively; 3) 75% of the neurons showed a significant increase in cutaneous thermosensitivity: their thresholds to slow heating of the skin changed from 43.7 +/- 0.7 to 40.3 +/- 0.7 degrees C (P < 0.005) and to slow cooling from 23.7 +/- 3.3 to 29.2 +/- 1.8 degrees C (P < 0.05); 4) dural receptive fields expanded within 30 min and cutaneous receptive fields within 2-4 h; and 5) ongoing activity developed in WDR and HT but not in LT neurons. Application of lidocaine to the dura abolished the response to dural stimulation but had minimal effect on the increased responses to cutaneous stimulation (suggesting involvement of a central mechanism in maintaining the sensitized state). Antidromic activation (current of <30 muA) of dura-sensitive neurons revealed projections to the hypothalamus, thalamus, and midbrain. These findings suggest that chemical activation and sensitization of dura-sensitive peripheral nociceptors could lead to enhanced responses in central neurons and that this central sensitization therefore could result in extracranial tenderness (mechanical and thermal allodynia) in the absence of extracranial pathology. The projection targets of these neurons suggest a possible role in mediating the autonomic, endocrine, and affective symptoms that accompany headaches.

On the origin of headaches.

Headache is one of the most common types of pain, but its causes remain poorly understood. The long-standing idea that some headaches, particularly migraine, might be caused by cerebral or cranial vasodilation has failed to find support in recent studies. Alternative hypotheses have focused on other processes that might be capable of activating or sensitizing sensory nerve fibres that innervate the blood vessels of the intracranial meninges.

Sensitization of meningeal sensory neurons and the origin of headaches.

The headaches that accompany certain intracranial pathologies (such as meningitis, subarachnoid haemorrhage and tumour) have been considered to result from mechanical or chemical stimulation of pain-sensitive structures of the intracranial meninges. Although the recurrent headache of migraine is of unknown origin and is not accompanied by an identifiable pathology, it shares with intracranial headaches features that suggest an exaggerated intracranial mechanosensitivity (worsening of the pain by coughing, breath-holding or sudden head movement). One possible basis for such symptoms would be a sensitization of meningeal afferents to mechanical stimuli. Previous studies of neuronal responses to meningeal stimulation have focused primarily on cells in the central portion of the trigeminal pathway, and have not investigated the possible occurrence of sensitization. We have recorded the activity of primary afferent neurons in the rat trigeminal ganglion that innervate the dural venous sinuses. Chemical stimulation of their dural receptive fields with inflammatory mediators both directly excited the neurons and enhanced their mechanical sensitivity, such that they were strongly activated by mechanical stimuli that initially had evoked little or no response. These properties of meningeal afferents (chemosensitivity and sensitization) may contribute to the intracranial mechanical hypersensitivity that is characteristic of some types of clinically occurring headaches, and may also contribute to the throbbing pain of migraine.

The peripheral antinociceptive effect of morphine in a rat model of facial pain.

The present study compared the peripheral and systemic antinociceptive effect of morphine on formalin-induced facial pain behavior in the rat. Formalin (5%, 50 microliters) was injected subcutaneously into the vibrissal pad of adult rats (250-300 g). Morphine sulfate at doses of 100-1000 micrograms was subcutaneously injected locally (same area) or systemically (in the neck), 30 min before, or simultaneously with, formalin. The typical biphasic face grooming response, consisting of an early phasic phase (0-6 min) and a delayed tonic phase (12-42 min), displayed by control animals, was suppressed by both local and systemic administration of morphine; this effect was dose dependent. However, the suppression of the early phase with local morphine administration 30 min before formalin could be significantly greater (49-52%) than with systemic administration, depending on the dose used. Administration of local morphine simultaneously with formalin produced up to 34% reduction in the early and an additional 32% reduction of the late phases of face grooming, compared to systemic injections. Local injection of naloxone (10 micrograms) almost completely reversed the antinociceptive effect of 1000 micrograms of morphine (early phase 85 +/- 7%, late phase 100 +/- 26% reduction), whereas the same dose of naloxone applied systemically (i.p.) produced only partial reversal (early phase 29 +/- 16%, late phase 36 +/- 1% reduction). This study further indicates that locally administered morphine can exert an analgesic effect superior to systemic administration in the case of inflammatory and non-inflammatory pain through a peripheral site of action. These results support the clinical use of peripheral opioid administration in the treatment of human painful conditions.

Fos expression in the medullary dorsal horn of the rat after chronic constriction injury to the infraorbital nerve.

Chronic constriction injury to the rat's infraorbital nerve (IoN-CCI) induces asymmetric face grooming directed to the injured nerve territory and, beginning at 7-12 days postoperative, hyperresponsiveness to mechanical stimulation in this territory (B.P. Vos, A.M. Strassman, and R.J. Maciewicz, 1994, J. Neurosci. 14:2708-2723). To examine central mechanisms involved in these behavioral alterations, changes in nonevoked and mechanical stimulation-evoked fos-like immunoreactivity (fos-LI) following IoN-CCI were quantified in the medullary dorsal horn. Following the appearance of hyperresponsiveness in IoN-CCI rats, experimental and matched sham-operated rats were anesthetized with urethane and received either no stimulation or repeated stimulation with either a 2- or 15-g von Frey hair applied to the hairy skin between vibrissae B3-4/C3-4 on the operated side. Unstimulated IoN-CCI rats had increased fos-LI in laminae I-IV of the ipsilateral medullary dorsal horn. In both groups, mechanical stimulation produced a distinct pattern of fos-LI in the ipsilateral medullary dorsal horn, the quantity of which was related to stimulus intensity. For both stimulus intensities, the total amount and the rostrocaudal spread of evoked fos-LI were significantly larger in IoN-CCI rats. In IoN-CCI rats, stimulation-evoked increases in fos-LI were proportionally larger in laminae I-II than in III-IV. This laminar effect was also present in sham-operated rats but only for 15-g stimulation. Neither condition nor stimulus intensity affected fos-LI in the contralateral medullary dorsal horn. Positive correlations were found between the behavioral parameters of increased trigeminal nociceptive activity and the total amount of fos-LI in the ipsilateral medullary dorsal horn. The results demonstrate that IoN-CCI induces significant alterations in the central processing of afferent signals, which may underlie behavioral manifestations of increased nociceptive activity.

The clinically tested N-methyl-D-aspartate receptor antagonist memantine blocks and reverses thermal hyperalgesia in a rat model of painful mononeuropathy.

This study tested the prophylactic and therapeutic efficacy of memantine (1-amino-3,5-dimethyl-amandate), a clinically tested N-methyl-D-aspartate (NMDA) antagonist on thermal hyperalgesia in a rat model of painful mononeuropathy. Persistent hyperalgesia induced by chronic constrictive injury (CCI) to the sciatic nerve was significantly reduced for up to 14 days by prophylactic administration of memantine (3.0 mg/kg) via i.p. implanted osmotic micropumps for a period of 7 days. Therapeutic i.p. injections of memantine (10 mg/kg) given on post-injury days 7 and 14 completely reversed existing hyperalgesia for a short period of 1 h. These results provide evidence that memantine produces long-term prophylactic and short-term therapeutic effects on thermal hyperalgesia in a model of painful mononeuropathy.

Distribution of Fos-like immunoreactivity in the caudal medullary reticular formation following noxious facial stimulation in the rat.

To investigate the topographic organization of nociceptive neurons in the caudal medullary reticular formation, the distribution of cells that exhibit c-fos expression was examined following a unilateral noxious facial stimulus: subcutaneous injection of formalin into the vibrissal pad of awake rats. Labelling for Fos-like immunoreactivity was present in a somatotopic distribution in a region of the lateral reticular formation adjacent to trigeminal nucleus caudalis, which corresponds approximately to lamina V of the medullary dorsal horn. Labelling in adjacent regions of the reticular formation showed no somatotopy but was predominantly ipsilateral. Contralateral labelling was concentrated ventrolaterally around the lateral reticular nucleus and dorsally near the nucleus of the solitary tract.

Anatomical properties of brainstem trigeminal neurons that respond to electrical stimulation of dural blood vessels.

Single unit recording studies in anesthetized cats have identified a population of neurons in the brainstem trigeminal complex that can be activated by stimulation of major dural blood vessels. Such dura-responsive neurons exhibit response properties that are appropriate for a role in the mediation of vascular head pain in that they typically exhibit nociceptive facial receptive fields whose periorbital distribution is similar to the region of referred pain evoked by dural stimulation in humans. In the present study, intracellular labelling with horseradish peroxidase was used to examine the anatomical characteristics of brainstem trigeminal neurons that respond to dural stimulation. A total of 17 neurons was labelled that responded to electrical stimulation of dural sites overlying the superior sagittal sinus or middle meningeal artery. Fourteen of these neurons also responded to electrical stimulation of the cornea. The neurons in this sample were located in the rostral two-thirds of the trigeminal nucleus caudalis and the caudalmost part of the nucleus interpolaris. Within caudalis, the neurons were located in the deeper part of the nucleus, primarily lamina V, and were concentrated ventrolaterally. The dendritic arborizations of the dura-responsive neurons typically exhibited a dorsolateral-to-ventromedial orientation and did not extend into the superficial laminae of caudalis. Dura-responsive neurons had axonal collaterals and boutons in the nucleus caudalis, nucleus interpolaris, the infratrigeminal region ventral to nucleus interpolaris, the nucleus of the solitary tract, and the medullary reticular formation. The axonal boutons within the trigeminal complex exhibited a ventrolateral distribution which largely overlapped the distribution of the somata. The results are consistent with previous evidence that dura-responsive brainstem trigeminal neurons may have a role in the mediation of dural vascular head pain and also indicate that such neurons may contribute to nociceptive processing within the dorsal horn.

Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat.

Neurophysiological studies have generally failed to find evidence of a specific ascending pathway for visceral nociception. However, pain that arises from deep or visceral tissues typically differs from cutaneous pain, particularly in its diffuse, poorly localized quality. In this study, the c-fos mapping technique was used in order to investigate possible differences in the distribution of central neurons activated by afferent pathways from cutaneous and deep tissues that may be related to the differing quality of the sensations they evoke. The distribution of neurons in the upper cervical and medullary dorsal horn that displayed fos-like immunoreactivity (fos-LI) was examined following mechanical stimulation of dural blood vessels (transverse and superior sagittal sinuses), and was compared to that found following mechanical, thermal, and chemical stimulation of facial sites. Dural stimulation was carried out Brevital anesthesia in rats that had received a chronic surgical exposure of the transverse and superior sagittal sinuses 2 d earlier. Localized mechanical stimulation of the dural surface of the transverse sinus produced a predominantly ipsilateral increase in the number of fos-LI neurons in the medullary and upper cervical dorsal horn (primarily laminae I and V), and in the transition region between the trigeminal nucleus caudalis and interpolaris. Stimulation of the superior sagittal sinus produced increases in fos-LI labeling that were generally smaller than those produced by transverse sinus stimulation. The distribution of fos-LI labeling in the dorsal horn induced by dural stimulation differed from that induced by facial stimulation in two ways. (1) Dural stimulation produced a more diffuse distribution of fos-LI than facial stimulation in the dorsal horn. Whereas facial stimulation produced a dense, localized zone of fos-LI labeling in the dorsal horn, dural stimulation produced fos-LI labeling that extended from the midlevel of caudalis to C2/C3, and also extended across a large portion of the ventrolateral-to-dorsomedial axis of the dorsal horn. This distribution roughly corresponds to the representation of most of the dorsal half of the head and face. (2) Dural stimulation produced a more restricted laminar distribution of fos-LI labeling than facial stimulation, in that the dural-induced labeling in the superficial dorsal horn was primarily restricted to lamina I, whereas facial stimulation typically induced substantial labeling in both lamina I and the outer part of lamina II. These differences in the central organization of the afferent pathways from dural and facial sites may contribute to the differences in the quality of sensations evoked by these pathways.

Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve.

Video recordings of free behavior and responses to mechanical facial stimulation were analyzed to assess whether chronic constriction injury (CCI) to the rat's infraorbital nerve (IoN) results in behavioral alterations indicative of neuropathic pain. A unilateral CCI was produced by placing loose chromic gut ligatures around the IoN. After CCI to the IoN, rats exhibited changes in both non-evoked and evoked behavior. Behavioral changes developed in two phases. Early after CCI (postoperative days 1-15), rats showed increased face-grooming activity with face-wash strokes directed to the injured nerve territory, while the responsiveness to stimulation of this area was decreased. Later after CCI (postoperative days 15-130), the prevalence of asymmetric face grooming was reduced but remained significantly increased compared to control rats. The early hyporesponsiveness was abruptly replaced by an extreme hyperresponsiveness: all stimulus intensities applied to the injured nerve territory evoked the "maximal" response (brisk head withdrawal, avoidance behavior plus directed face grooming). This response was never observed in control rats. Concurrently, IoN ligation rats showed a limited increase in the responsiveness to stimulation of the contralateral IoN territory, and around postoperative days 30-40 the responsiveness to stimulation of facial areas outside the IoN territories also increased. The hyperresponsiveness to stimulation of the ligated IoN territory slightly decreased from 60 d postoperative. Throughout the study, IoN ligation rats showed decreased exploratory behavior, displayed more freezing-like behavior, had a slower body weight gain, and a higher defecation rate, compared to control rats. The behavioral alterations observed after CCI to the IoN are indicative of severe sensory disturbances within the territory of the injured nerve: mechanical allodynia develops after a period of relative hypo-/anesthesia during which behavioral signs of recurrent spontaneous, aversive (possibly painful) sensations (paresthesias/dysesthesias) are maximal.

The effects of the clinically tested NMDA receptor antagonist memantine on carrageenan-induced thermal hyperalgesia in rats.

This study tested the prophylactic and the therapeutic efficacy of memantine (1-amino-3,5-dimethyl-amandate), a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in suppressing carrageenan-induced thermal hyperalgesia in rats. Rats were injected with 0.1 ml of 1% carrageenan solution s.c. into the right hindpaw, and exhibited hyperalgesia in the injected paw as evidenced by a significant reduction of withdrawal latencies from baseline 1, 3, 5, and 24 h following carrageenan. Prophylactic injection of memantine, 10 and 15 mg/kg, significantly suppressed the hyperalgesia 1, 3, and 5 h post-carrageenan, with maximal effects of 70% (10 mg/kg) and 90% (15 mg/kg) at 1 h post-carrageenan. Therapeutic injection of 10 mg/kg of memantine (2.5 h post-carrageenan) had no effect. The 15 mg/kg dose produced a small effect (peak of 44%) at 3.5 h but not at a statistically significant level, and had no effect 5 h post-carrageenan. This study provides evidence that memantine produces primarily a prophylactic effect (and has only a tendency to produce a therapeutic effect) on carrageenan-induced hyperalgesia at doses that do not significantly alter other motor behaviors.

Fos-like immunoreactivity in the superficial medullary dorsal horn induced by noxious and innocuous thermal stimulation of facial skin in the rat.

1. To examine further the ability of different classes of nociceptive and nonnociceptive primary afferent neurons to induce c-fos expression in central neurons, fos-like immunoreactivity was examined in the medullary dorsal horn (laminae I-IV) of the rat after facial application of a range of warming and cooling thermal stimuli. Urethan-anesthetized rats received 15 30-s thermal pulses (53, 50, 47, 41, 25, or 10 degrees C) applied to the vibrissal pad over a period of 30 min and were perfused 2 h after the end of stimulation. 2. Stimulation of 41 degrees C produced no significant increase in the number of fos-LI-labeled cells in lamina I or II compared with control (35 degrees C) animals. 3. Stimulation of 47 degrees C produced a significant increase in the number of fos-LI-labeled cells in both laminae I and II. Stimulation of 50 degrees C produced a significant increase in labeling, compared with that produced by 47 degrees C, which was primarily in lamina II. Stimulation of 53 degrees C produced no further increase in the number of labeled cells, compared with that produced by 50 degrees C, in lamina I or II. 4. In the cooling direction, 25 degrees C produced a significant increase in labeling above control levels in both lamina I and II, whereas 10 degrees C produced a further increase compared with 25 degrees C, which was restricted to lamina I. 5. None of the stimuli produced a significant increase in labeling in laminae III-IV. 6. The results are interpreted as providing evidence that low-threshold cold receptors, high-threshold cold receptors, and nociceptors are capable of inducing fos expression in dorsal horn neurons, whereas warm receptors are relatively ineffective. The results also provide evidence that neurons that receive input from C polymodal nociceptors are present in both laminae I and II, as are neurons that receive input from low-threshold cold receptors. Neurons that receive input from high-threshold cold receptors, but not from low-threshold cold receptors, appear to be located preferentially in lamina I. The shape of the curve relating fos-LI labeling to stimulus temperature in the warming direction is consistent with the expected pattern of recruitment of primary afferent nociceptors.

Somatotopic and laminar organization of fos-like immunoreactivity in the medullary and upper cervical dorsal horn induced by noxious facial stimulation in the rat.

The distribution of fos-like-immunoreactivity (fos-LI) in the medullary and upper cervical dorsal horn was examined following noxious facial stimulation, in order to evaluate the use of fos as a marker for neuronal activation in trigeminal nociceptive pathways. Control animals that received urethane anesthesia and no facial stimulation showed substantial bilateral labeling in the trigeminal complex that was restricted to one rostrocaudal level, at the transition between the medullary dorsal horn (nucleus caudalis) and nucleus interpolaris. Noxious mechanical stimulation (pinch) of different facial sites produced labeling in the ipsilateral dorsal horn whose distribution varied predictably with the rostrocaudal and dorsoventral position of the facial stimulation site, such that rostral facial sites were represented rostrally in the dorsal horn and dorsal sites were represented ventrolaterally. The cornea was exceptional among the facial stimulation sites in that it had a specific representation at two distinct rostrocaudal levels, in C1 and the interpolaris-caudalis transition region; the position of the rostral peak was somatotopically inappropriate, based on the representation of other facial sites. The proportion of labelling in laminae III-IV relative to laminae I-II was higher with noxious mechanical stimulation than with noxious thermal (55 degrees C) or chemical (subcutaneous injection of capsaicin) stimulation. The proportion of labelling in laminae III-IV produced by electrical stimulation of the infraorbital nerve was no greater than that produced by pinch. The results suggest that fos-LI mapping can be a useful method for the investigation of somatotopy but is subject to serious limitations when used for the investigation of laminar organization. The results also suggest that the interpolaris-caudalis transition region may have properties that are distinct from those of the rest of the trigeminal complex, possibly related to an involvement in autonomic function.