Injection of a dilute solution of formalin into a rat hindpaw produces a biphasic nociceptive response consisting of an early phase during the first 5 min after formalin injection and a later phase starting after 15 min and lasting for 40-50 min. The period between the two phases of nociceptive responding is generally considered to be a phase of inactivity. We compared the nociceptive behaviors produced by a single hindpaw injection of 50 microl of formalin with those produced by two formalin injections given 20 min apart. A single formalin injection at concentrations of either 1 or 2.5%, produced the typical biphasic nociceptive responses. In rats given a second injection of either 1 or 2.5% formalin 20 min after the first, a triphasic response occurred, with a second diminution of nociceptive behavior observed between 10 and 15 min after the second injection. When a second injection of 2.5% formalin was given 5 min after the first, there was no difference from the scores in the group given only one injection. In electrophysiological experiments on single dorsal horn nociceptive neurons, a second injection of 2.5% formalin into the peripheral cutaneous receptive field, 40 min after the first and at the same site of injection as the first formalin injection, depressed neuronal activity for approximately 15-20 min. From the data it can be concluded that the interphase period in the formalin test is due to active inhibition. Furthermore, the inhibition which we are reporting here is independent of the concentration of formalin used, and thus of any so-called inflammatory component. The lack of additive nociceptive effects when the inter-injection interval was only 5 min, suggests that a maximum inhibition was provoked by 2.5% formalin; it can also be concluded that the active inhibition is of overriding importance physiologically, compared with the nociceptive activity. Data from parallel electrophysiological experiments on spinal dorsal horn neurons demonstrated a diminution in excitability after a second formalin injection into the cutaneous receptive field. As these data were obtained from pentobarbital-anesthetized, spinalized rats, the data suggest further that the two excitatory phases and the active inhibition are mediated by spinal mechanisms and that the inhibition is not under regulation of a GABAergic mechanism. The implication of the results is not only further evidence of physiological control mechanisms interacting to regulate pain, but they also indicate the overriding priority of intrinsic inhibitory mechanisms. This, in turn, suggests that the clinical management of pain may be enhanced by efforts to potentiate mechanisms of inhibition.
1 Nerve injury often produces long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to treatment, being only partially relieved by clinical analgesics, and often insensitive to morphine. With the aim of assessing its therapeutic potential, we examined the e ect of antisense oligonucleotide knockdown of spinal metabotropic glutamate receptor 1 (mGluR 1 ) in neuropathic rats. 2 We chronically infused rats intrathecally with either vehicle, or 50 mg day 71 antisense or missense oligonucleotides beginning either 3 days prior to or 5 days after nerve injury. Cold, heat and mechanical sensitivity was assessed prior to any treatment and again every few days after nerve injury. 3 Here we show that knockdown of mGluR 1 signi®cantly reduces cold hyperalgesia, heat hyperalgesia and mechanical allodynia in the ipsilateral (injured) hindpaw of neuropathic rats. 4 Moreover, we show that morphine analgesia is reduced in neuropathic rats, but not in shamoperated rats, and that knockdown of mGluR 1 restores the analgesic e cacy of morphine. 5 We also show that neuropathic rats are more sensitive to the excitatory e ects of intrathecally injected N-methyl-D-aspartate (NMDA), and have elevated protein kinase C (PKC) activity in the spinal cord dorsal horn, two e ects that are reversed by knockdown of mGluR 1 . 6 These results suggest that activity at mGluR 1 contributes to neuropathic pain through interactions with spinal NMDA receptors and PKC, and that knockdown of mGluR 1 may be a useful therapy for neuropathic pain in humans, both to alleviate pain directly, and as an adjunct to opioid analgesic treatment.
The contribution of the intracellular messengers nitric oxide, arachidonic acid and protein kinase C to persistent nociception in response to tissue injury in rats was examined following the subcutaneous injection of formalin into the hindpaw. Formalin injury-induced nociceptive behaviours were reduced by intrathecal pretreatment with inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), arachidonic acid (dexamethasone) or protein kinase C [protein kinase C (19-26) and 1-95-(isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride, H-7]. Each of these agents affected the tonic, but not the acute, phase of the formalin response. Furthermore, none of these agents affected mechanical or thermal flexion reflex thresholds in rats not injected with formalin. Conversely, formalin-induced nociceptive responses were enhanced by stimulators of nitric oxide (sodium nitroprusside), arachidonic acid metabolism (arachidonic acid) or protein kinase C [(+/-)-1-oleoyl-2-acetyl-glycerol], and were slightly reduced by inositol trisphosphate. Mechanical flexion reflexes were also reduced by arachidonic acid, while thermal flexion reflexes were reduced after treatment with sodium nitroprusside, arachidonic acid or [(+/-)-1-oleoyl-2-acetyl-glycerol]. The enhancement of formalin nociceptive behaviours (hyperalgesia) in rats treated with L-glutamate or substance P was reversed by pretreatment with inhibitors of nitric oxide (L-NAME), arachidonic acid (dexamethasone) or protein kinase C (H-7). The results suggest that central sensitization and persistent nociception following formalin-induced tissue injury, and the hyperalgesia in the formalin test induced by L-glutamate and substance P, are dependent on the intracellular messengers nitric oxide, arachidonic acid and protein kinase C.
Central poststroke pain (CPSP), formerly known as thalamic pain syndrome of Déjerine and Roussy, is a central neuropathic pain occurring in patients affected by stroke. It is one manifestation of central pain, which is broadly defined as central neuropathic pain caused by lesions or dysfunction in the central nervous system. Thalamic pain was first described 100 years ago by Déjerine and Roussy and has been described as "among the most spectacular, distressing, and intractable of pain syndromes". CPSP is characterized by constant or intermittent pain and is associated with sensory abnormalities, particularly of thermal sensation. While the pain is frequently described as burning, scalding, or burning and freezing, other symptoms are usually vague and hard to characterize, making an early diagnosis particularly difficult. In fact, those who develop CPSP may no longer be under the care of health care professionals when their symptoms begin to manifest, resulting in misdiagnosis or a significant delay before treatment begins. Diagnosis is further complicated by cognitive and speech limitations that may occur following stroke, as well as by depression, anxiety and sleep disturbances. Patients may also exhibit spontaneous dysesthesia and the stimulus-evoked sensory disturbances of dysesthesia, allodynia and hyperalgesia. The present study offers a historical reference point for future clinical and basic research into this elusive type of debilitating pain.
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