Pain
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Recent studies indicate that sustained opioid administration produces increased expression of spinal dynorphin, which promotes enhanced sensitivity to non-noxious and noxious stimuli. Such increased "pain" may manifest behaviorally as a decrease in spinal antinociceptive potency. Here, the possibility of similar mechanisms in the antinociception of spinal cannabinoids was explored. ⋯ Daily MK-801 pretreatments, prior to WIN 55,212-2 injection, also produced a significant block of antinociceptive tolerance. These data suggest that like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance.
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The spared nerve injury (SNI) model involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the sural nerve intact. The changes in pain-like sensation of the injured animals appear to correlate with a number of symptoms presented in human patients with neuropathic pain syndromes. In order to characterise the SNI model pharmacologically, reflex nociceptive responses to mechanical and cold stimulation were measured after systemic administration of morphine, mexiletine, gabapentin and the glutamate receptor antagonists, MK-801 and NS1209. ⋯ Gabapentin (100 mg/kg, i.p.) significantly alleviated mechanical allodynia for at least 3h, while no significant effects were observed for either mechanical hyperalgesia or cold allodynia. In contrast, the NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) and the AMPA receptor antagonist NS1209 (6 mg/kg, i.p.) did not relieve any of the pain-like behaviours of the SNI animals. The present study has shown that a variety of drugs with proven analgesic potency in other models of chronic pain, have differing analgesic profiles in the SNI model of neuropathic pain.
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A noxious cold stimulus can evoke multiple sensations each occurring with a different time course. We have performed psychophysical studies to identify the time course of five sensations evoked by a noxious cold stimulus applied to the hand. Subjects continuously rated either pain, ache, cold, heat or prickle sensations throughout repeated presentations of a noxious cold stimulus (3 degrees C) from a neutral (32 degrees C) baseline. ⋯ Identification of these temporal profiles could provide clues to their underlying mechanisms. The temporal dissociation of these sensations will also enable neuroimaging studies of the cortical mechanisms associated with these sensations. Thus our results constitute a first step toward identifying the distinct modes of neural activity associated with different types of pain sensation.
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Two unilateral injections of pH 4.0 saline into the gastrocnemius muscle result in a bilateral decrease in mechanical withdrawal threshold after the second injection. This decrease is significant by 4h and lasts through 1 week. The purpose of this study was to characterize the involvement of both N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the spinal cord dorsal horn in the development and maintenance of mechanical hyperalgesia from repeated intramuscular injections of acidic saline. 2-amino-5-phosphonovaleric acid (AP5) (2-20 nmol, 10 microl, pH 7) or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) (1-10 nmol, 10 microl, pH 8-9) was administered intrathecally to the lumbar spinal cord to block NMDA and non-NMDA ionotropic glutamate receptors in the dorsal horn, respectively. ⋯ Blockade of non-NMDA glutamate receptors in the spinal cord dorsal horn prior to either the first or second intramuscular injection of pH 4.0 saline had no effect on the development of mechanical hyperalgesia. However, spinal injection of NBQX 1 week after the second intramuscular injection of pH 4.0 saline resulted in an increase in mechanical withdrawal thresholds when compared to vehicle controls. These data suggest that both NMDA and non-NMDA glutamate receptors are involved in the maintenance of chronic, muscle-induced hyperalgesia.
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Two drugs used in combination may produce enhanced or reduced effects. The degree of enhancement or reduction is measured from the interaction index (gamma), a quantity that indicates the changed potency of the combination. The index is therefore a quantitative marker for the drug combination and effect metric used. ⋯ In some cases, the relative potency of the constituent drugs is the same at all effect levels. When this is so, it is shown that the interaction index can be measured by either an isobolar or an alternate method that is illustrated here. These calculations demonstrate that these different methods of analysis yield the same value of gamma, and do so with comparable precision.