Nociceptive Reactions Research Articles

Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation.

Single-unit recordings were made under moderate gaseous anaesthesia in the hindpaw representation area of the two primary somatosensory motor cortices (SmI) of rats (n = 58) rendered mononeuropathic by four loose ligatures placed around one common sciatic nerve 2-3 weeks beforehand. The rats exhibited clear hyperalgesia and allodynia from the paw with the ligated sciatic nerve, to both mechanical and thermal stimuli. From the tested neuronal population (n = 640), about the same proportion could be activated by somatic stimuli in each cortex: 165/362 (45%) in the cortex contralateral to the ligated sciatic nerve (Cc), 105/278 (37%) in the cortex ipsilateral to the ligated sciatic nerve (Ci). Neurones driven by light touch, exhibited RFs strictly contralateral to the recording sites. Their proportion and response characteristics were similar regardless of recording side. However, the number of neurones with RFs in the sciatic nerve territory was above 95% in the Ci, and was dramatically reduced to 43% in the Cc. By contrast, the number of neurones with RFs supplied by the saphenous nerve reached 57% on this side. Although the RF size of all the neurones appeared roughly normal, there were fewer Cc than Ci neurones with RFs located on the paw itself and with RFs of extremely small size in the sciatic nerve territory. The proportion of neurones responding to a joint stimulus was significantly higher in the Cc than in the Ci. The neuronal responses to joint stimuli of the paw with the ligated sciatic nerve were significantly more sustained than those recorded in the Ci and elicited from the normal paw. The proportion of neurones driven by mechanical stimulation which gave rise to nociceptive reactions in freely moving animals, i.e. "nociceptive" neurones, was comparable in each cortex. However, half of the Cc neurones exhibited paroxysmal discharges occurring without intentional stimulation and of long duration (1 min to several minutes). Only 66% of Cc but 93% of Ci "nociceptive" neurones were exclusively activated by pinch. The remaining Cc neurones were also activated by applying moderate pressure to the paw with the ligated nerve. Pinch responses from the paw with the ligated nerve were often more intense and of longer duration than responses elicited from the intact paw. The "nociceptive" Cc neurones were especially sensitive to thermal stimuli of 39-44 degrees C when the stimuli were applied to the paw with the ligated nerve. They also responded vigorously to a 10 degrees C stimulus applied to this paw.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy

1. Single-unit recordings were made, under moderate gaseous anesthesia (33% O2-66% N2O + 0.5/0.6% halothane), in the ventrobasal (VB) thalamic complex of rats (n = 42) with a mononeuropathy created 2-3 wk beforehand, by four loose ligatures around the common sciatic nerve. Before the recording session, three behavioral nociceptive tests to both mechanical and thermal stimuli revealed that these rats exhibited clear hyperalgesia (excessive reactions to noxious stimuli) and allodynia (nociceptive reactions to stimuli usually perceived as nonnoxious). 2. Neurons, characterized by their responses to manual mechanical stimuli, were classified into two groups: group 1 neurons exclusively driven by light tactile stimuli applied to the receptive field (RF), strictly contralateral to the recording site; and group 2 neurons, driven by sustained pinch applied to a large RF, often bilateral. 3. From the total population of neurons (n = 386), only those responding to stimuli applied to one posterior paw were studied; the proportion (35-40%) of these cells was comparable in each of the two VB: n = 93/262 and 44/124 in the VB contralateral (VBc) and ipsilateral (VBi) to the damaged nerve, respectively. The proportions of each functional group of neurons (group 1 or 2) were also similar on each side. 4. For all group 1 neurons the RFs size was comparable to that observed in normal rats. In the VBi the responses of these neurons presented the classical response pattern observed for VB neurons involved in touch transmission, as did the VBc group 1 neurons with RFs in the saphenous (Sa) territory. In sharp contrast, activities of VBc group 1 neurons with RFs in the sciatic (Sc) nerve territory exhibited several abnormalities: higher background activity, fading of the response with repetitive stimulation, and afterdischarges outlasting the applied stimulus. 5. As in normal rats, 52% of VB group 2 neurons exhibited bilateral symmetrical RFs. Their responses to mechanical stimuli were often greater for stimuli applied to the affected paw, and some of them could be activated by moderate pressure to this paw. Heat responses also illustrated the profound increased sensitivity of the lesioned side, and the activation threshold to thermal stimulation of these group 2 neurons was lowered by 4-6 degrees C compared to normal values. In addition, these neurons responded to immersion of the lesioned paw in a 10 degrees C water bath, a stimulus that was ineffective when applied to the opposite paw.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tractotomy on nociceptive reactions induced by tooth pulp stimulation in the rat

The effects of a trigeminal tractotomy on nociceptive reactions induced by electrical stimulation of an inferior incisor were studied in freely moving rats. Behavioral tests were based on the observation of three reactions: jaw opening reflex, face scratching with forepaws, and head rotation toward the stimulated side. These reactions appear successively when the stimulation intensity increases. The results were evaluated by comparing a test group with a sham-operated group. Both groups were prepared surgically in the same way but only the former had undergone tractotomy. The results were as follows: The threshold of the jaw opening reflex triggered by stimulation of the tooth pulp ipsilateral to the tractotomy was not modified; however, the threshold of the face-scratching and the head rotation reactions rose ( P ≤ 0.05) after tractotomy. These data suggest that the rostral part of the trigeminal sensory complex is involved in oral nociception. However, the modification of the face-scratching and head rotation thresholds reveals that the subnucleus caudalis also participates in this function when a certain level of pain is reached. The thresholds of the three nociceptive reactions evoked by stimulation of the contralateral tooth pulp were significantly lower in the test group than those in the sham-operated group ( P ≤ 0.001), which is interpreted as being indicative of an modulating effect of the subnucleus caudalis on the contralateral trigeminal sensory complex. This effect was probably revealed by the use of a sham-operated group as a control.

S-9-2 - Nociceptive reactions and its regulation involved in the activity of primary sensory neurons at the periphery.

S-9-2 - Nociceptive reactions and its regulation involved in the activity of primary sensory neurons at the periphery.

Noxious stimuli excite neurons in nucleus submedius of the normal and arthritic rat

Anatomical studies have revealed the existence of an ascending pathway originating in the spinal cord and medullary dorsal horn, relaying in nucleus submedius (Sm) in medial thalamus and terminating in ventrolateral orbital cortex. It has been suggested that this pathway may be involved in the transmission of nociceptive information. In the present study extracellular recordings were obtained from neurons in Sm of anesthetized arthritic and normal rats. Mechanical and thermal stimuli were delivered to various regions of the body to determine the types of somatic stimuli which could activate Sm neurons. Over 40% of the 146 neurons studied responded to somatic stimuli. In the normal rats only high intensity mechanical and thermal stimuli were effective in inducing responses. In the arthritic rats lower intensity mechanical stimuli, joint movements and high intensity thermal stimuli were effective. Such stimuli produce nociceptive reactions in the freely moving arthritic rat. Almost all the responses were excitatory and generally lasted the entire duration of the 15-s stimuli employed. In some cases after-discharges were present. The receptive fields of the neurons were in almost all cases large and bilateral. These findings support the hypothesis that Sm may be involved in mediating the affective-motivational aspects of pain.

Different effects of norepinephrine and serotonin on the electrical toe stimulation-induced reflexes in the rat spinal cord

1. 1. Electrical toe stimulation was shown to elicit reflex potentials in the ipsilateral common peroneal nerve in the rat. 2. 2. This reflex consisted of the spinal reflex and the spino-bulbo-spinal reflex (SBS reflex). 3. 3. Administration of norepinephrine into the subarachnoid space enhanced the spinal reflex but depressed the SBS reflex. On the other hand, serotonin enhanced both reflexes. 4. 4. These different effects of norepinephrine and serotonin suggest different control of nociceptive reactions by these biogenic amines.

Possible Use of Capsaicin in Pain Therapy

Abstract Capsaicin, the active ingredient in hot peppers, produces a long-lasting reduction of nociceptive reactions in rodents through a selective toxic action on afferent C-fibres. Immediate effects on C-fibre conduction are also found in other mammalian species and a reduction in nociceptive responses from human skin occurs following topical application. Direct application to nerve trunks may be expected to produce a useful degree of regional analgesia in man. Since this effect would occur without any anaesthesia or paralysis, it appears worth investigating as a treatment for pain of peripheral origin in man.

Experimental study of the effect of captopril on nociceptive reactions

Experimental study of the effect of captopril on nociceptive reactions

Is electrical stimulation of the rat incisor an appropriate experimental nociceptive stimulus?

The purpose of this study was (i) to determine whether or not tooth pulp stimulation in the rat can selectively activate the pulp nerve fibers without excitation of the periodontium and (ii) to decide if the nerve fibers situated in the pulp of the rat's incisor are involved in the nociceptive reactions caused by an intrapulpal stimulation. The experiments were carried out on 20 awake and freely moving Sprague-Dawley rats. Bipolar stimulating electrodes were inserted into the pulp of the left lower incisor and in the right incisor after removal of the pulp. Special cares were taken to avoid, on the right side, direct stimulation of the stump of the apical nerve. The jaw opening reflexes were recorded from the digastric muscles ipsilaterally to the stimulated teeth and the thresholds were compared. Using the same animals, four typical and reproducible nociceptive behavioral reactions caused by a long tooth pulp stimulation were also observed (shock of 0.5 ms at 50 Hz during 1 s). The stimulus intensity was progressively increased, and the threshold of each reaction was recorded. For each of the 20 rats tested, the jaw opening reflex and the nociceptive reactions did not disappear after removal of the pulp, but the threshold of the responses to the stimulation of the nonvital tooth were significantly above the threshold of the responses to the stimulation of the vital incisor. The conclusion was (i) tooth pulp stimulation activates the periodontal nerve fibers in the rat, and (ii) stimulation of the incisor pulp is significant in pain study in the rat because the thresholds of the jaw opening reflex and the nociceptive reactions were increased after the tooth pulp tissue was removed.

The effect of capsaicin on afferent nerves and temperature regulation of mammals and birds

1. 1.|The impairment of nociception, warm reception and temperature regulation by capsaicin relates to the particular effect of the drug upon unmyelinated sensory nerve fibres which contain substance P and/or somatostatin. 2. 2.|Capsaicin also activates and subsequently desensitizes warm sensitive neurones in the hypothalamus, which contributes to impaired temperature regulation at high ambient temperatures. 3. 3.|Birds are highly insensitive to capsaicin. The threshold concentration for nociceptive reactions is about 1000–10,000 times that of mammals; temperature regulation was not impaired by doses up to 1 g/kg body weight. 4. 4.|The resistance of birds to capsaicin might be due to functional differences between mammals and birds in neuropeptide-containing neurones.

Morphine antagonizes inhibitory controls of nociceptive reactions, triggered by visceral pain in the rat

The interaction between morphine analgesia and the heterotopic hypoalgesic effects induced by visceral pain was investigated using a behavioral approach in the rat. Both systemic morphine and a dull pain of peritonel-visceral origin (induced by i.p. phenylbenzoquinone, PBQ) increase the threshold for vocalization to tail-shock. The question of the interaction between these two factors was assessed by administering morphine during the period of increase in threshold induced by PBQ. Not only did we find that morphine did not increase the threshold further, but, indeed, very significantly decreased it, with the more obvious effect being observed for a moderate dose (0.33 mg/kg, i.v.). It is concluded that morphine antagonizes the heterotopic hypoalgesic effects of visceral pain. These results do not support the hypothesis that morphine increases inhibitory controls of pain triggered by noxious inputs.

A critical analysis of the experimental evaluation of nociceptive reactions in animals.

Because of the complexities of the central nervous system compounded with the ambiguities of interpreting the sensation of and reaction to "pain" in animals, available techniques for experimental evaluation of nociception to various types of stimuli are crude. Simple methods are often associated with artifacts that affect both the qualitative and the quantitative outcome of the test. It is therefore mandatory to control every detail of the experimental protocol. Further, the acuity expected from the experimenter to observe the animals during the test cannot be overemphasized. Additionally the test procedure should not inflict excessive suffering to the animals. It is the purpose of this review to highlight some of the "safeguard" measures to be adopted in order to avoid false-positive and false-negative results and erroneous interpretations and conclusions.

Non-opiate analgesia following stressful acoustic stimulation

The change in the nociceptive reactions of rats was characterized after stressful acoustic (115 dB) stimulation. Acoustic loading for five minutes resulted in considerable analgesia in the hot-plate test, whereas a significant analgesic response was not observed in the tail-flick test. The analgesic reaction after acoustic stimulation was resistant to naloxone pretreatment and was also found in morphine-tolerant rats, but the acute thermoregulatory and analgesic effects of morphine were greatly potentiated by simultaneous acoustic loading. Substance P or cholecystokinin treatment likewise failed to prevent the analgesic effect of auditory stimulation. No tolerance developed to the analgesic effect on repeated stressing. Diltiazem, a slow calcium channel blocker, facilitated the analgesia. The data suggest a stress-induced analgesia with obviously non-opiate properties, although an indirect involvement of opiate effects could not be excluded.

Effects of N-methylnaloxone and N-methylanaltrexone on nociception and precipitated abstinence in mice

Subcutaneous administrations of naloxone and naltrexone have already been shown to enhance nociceptive reactions in mice. The present study was undertaken to examine the effects of N-methylnaloxone and N-methylnaltrexone on nociception using the hot plate test (dose range: 0.3 to 30 mg kg −1s.c.). The latter compounds were selected to differentiate the central and peripheral components of hyperalgesia. Unlike naloxone, N-methylnaloxone did not produce hyperalgesia. Similarly low doses of N-methylnaltrexone did not enhance the jumping response. However, a high dose of N-methylnaltrexone (30 mg kg −1s.c.) significantly reduced the jumping latencies 2h after its administration. This phenomenon indicated that it might be converted to an active metabolite. Further, N-methylnaloxone and N-methylnaltrexone were very weak in precipitating the signs of abstinence in mice rendered acutely dependent on morphine. Two factors, poorer penetration into the CNS and steric hindrance, might render the N-methylated antagonists weak. Hence, both these factors should be considered when intrepreting the effects after quaternary derivatives of opioid antagonists.

Quaternary narcotic antagonists' relative ability to prevent antinociception and gastrointestinal transit inhibition in morphine-treated rats as an index of peripheral selectivity

Single doses of naloxone (0.025 to 0.5 mg/kg) or of one of four quaternary narcotic antagonists (i.e. nalorphine allobromide, nalorphine methobromide, naloxone methobromide or naltrexone methobromide, 1 to 60 mg/kg) were given s.c. to rats before morphine, 5 mg/kg i.v. In the absence of antagonists morphine reduced G.I. transit of a charcoal meal to about 15% of drug-free controls and consistently delayed nociceptive reactions (55°C hot plate) in all animals. Doses of antagonists slightly reducing morphine antinociception (centrally effective = A) and restoring G.I. transit to about 50% of drug-free rats (peripherally effective = B) were estimated. The A:B ratio, indicating peripheral selectivity, was at least 8 for any of the quaternary antagonists given 10 min before morphine, but prolonging this interval may have resulted in a lower figure (i.e. less peripheral selectivity) because of reduced A and increased B. This was definitely so for naltrexone methobromide (A:B, > 60 at 10 min, about 1 at 80 min) and was not apparent for nalorphine methobromide according to available data, which for nalorphine allobromide and to a lesser extent for naloxone methobromide showed only an increase in B at intervals longer than 10 min. Both morphine-induced antinociception and inhibition of G.I. transit were reduced by naloxone at the lower doses tested and were fully prevented at the higher. These findings indicate that, unlike naloxone, the investigated quaternary narcotic antagonists are interesting prototype drugs for selective blockade of opiate receptors outside the CNS, although certain critical aspects, possibly biological N-dealkylation to the corresponding tertiary antagonists, condition peripheral selectivity.

The effect of pituitary removal on pain regulation in the rat

The effects of hypophysectomy (HX) on pain regulation in basal and in various stressful situations were investigated in the rat. Pain sensitivity was assessed by measuring the thresholds of 3 nociceptive reactions (tail withdrawal, vocalization, vocalization afterdischarge) following electrical stimulation of the tail. The completeness of HX and the integrity of hypothalamus were verified in each HX rat. (1) Baseline pain thresholds were lower in HX rats than in sham-operated animals; (2) naloxone (Nx) hyperalgesia was only slightly altered by HX; (3) different types of stress induced different types of changes in nociception i.e. analgesia or hyperalgesia. The influence of HX varied according to the stress: it increased hyperalgesia, reduced analgesia, or had no effect at all. These results indicate that in the rat: (i) the pituitary participates in the regulation of basal pain sensitivity, probably through analgesic factors; (ii) Nx hyperalgesia results essentially from an antagonism of endogenous opioids originating in the CNS and not in the pituitary; and (iii) the pain regulatory processes engaged in adaptation to stressful stimuli involve the CNS and the pituitary in variable proportions depending upon the nature of the stress.

Human nociceptive reactions: effects of spatial summation of afferent input from relatively large diameter fibers : Brain Res., 201 (1980) 465–470

Human nociceptive reactions: effects of spatial summation of afferent input from relatively large diameter fibers : Brain Res., 201 (1980) 465–470

Nociceptive reactivity and precipitated abstinence in hypophysectomized rats.

Nociceptive reactions were determined using the hot plate technique (55 degrees C) in sham-operated and hypophysectomized rats. No significant differences were noticed in the latencies to lick, jump, or escape between the two groups. These experiments indicate that pituitary endorphins are not the sole endogenous substances involved in the regulation of thermonociception. In hypophysectomized rats rendered acutely dependent on morphine, following naloxone, some signs of precipitated abstinence (chewing and teeth chattering) were significantly diminished, some others (abnormal posture, body tremor and pilo-erection) were significantly enhanced, and many others (urination, paw shakes, body shakes, diarrhoea, jump, rearing, eye blinking, head shakes and grooming) were not modified. These observations indicate that the pituitary has a complex role in the expression of signs of abstinence. However, concomitant lesions of the adjacent areas such as the hypothalamus might have also contributed to the observed modifications of the abstinence signs. Hence, it may be advisable always to interpret the results obtained with hypophysectomized rats with some caution.

NOCICEPTIVE REACTIVITY AND PRECIPITATED ABSTINENCE IN HYPOPHYSECTOMIZED RATS

Nociceptive reactions were determined using the hot plate technique (55°C) in sham-operated and hypophysectomized rats. No significant differences were noticed in the latencies to lick, jump, or escape between the two groups. These experiments indicate that pituitary endorphins are not the sole endogenous substances involved in the regulation of thermonociception. In hypophysectomized rats rendered acutely dependent on morphine, following naloxone, some signs of precipitated abstinence (chewing and teeth chattering) were significantly diminished, some others (abnormal posture, body tremor and pilo-erection) were significantly enhanced, and many others (urination, paw shakes, body shakes, diarrhoea, jump, rearing, eye blinking, head shakes and grooming) were not modified. These observations indicate that the pituitary has a complex role in the expression of signs of abstinence. However, concomitant lesions of the adjascent areas such as the hypothalamus might have also contributed to the observed modifications of the abstinence signs. Hence, it may be advisable always to interpret the results obtained with hypophysectomized rats with some caution.

Endogenous morphines and pain.

The involvement of endogenous morphines (enkephalins and endorphins) in the regulation of pain is demonstrated by the following experimental evidence: (a) their analgesic activities; (b) their distribution in the central nervous systems; (c) the effects of their modifiers, especially of their antagonists, on nociceptive reactions and (or) on various types of analgesia; (d) rare modifications of their brain levels in pain and (or) analgesic states. Besides the well-known facts, the following items are particularly stressed: the functional roles of hypothalamic structures and of the pituitary, the effects of antagonists, the variety of analgesia following noxious and (or) stressful stimuli, genetic and environmental factors, endogenous antinociceptive substances other than opioids, relations with biogenic amines. As a whole, endogenous morphines apparently filter the particular important sensory input represented by nociception and control the reactions to pain, allowing for adjusted behaviour, if the stimuli are avoidable, or for prevention or at least delay of exhaustion if the stimuli are unavoidable.